Prodrugs of thrombin inhibitors

ABSTRACT

The present invention relates to prodrugs of pharmacologically active five-membered heterocyclic amidines from which are produced in vivo compounds which are competitive inhibitors of trypsin-like serine proteases, in particular thrombin and kininogenases such as kallikrein, to the preparation thereof and to the use thereof as medicines. The invention also relates to pharmaceutical compositions which comprise the prodrugs of the active compounds as ingredients, and to the use of the compounds as thrombin inhibitors, anticoagulants and as antiinflammatory agents.

The present invention relates to prodrugs of pharmacologically activefive-membered heterocyclic amidines from which are produced in vivocompounds which are competitive inhibitors of trypsin-like serineproteases, in particular thrombin, and kininogenases such as kailikeinsto the preparation thereof and to the use thereof as medicines. Theinvention also relates to pharmaceutical compositions which comprise theprodrugs of the active compounds as ingredients, and to the use of thecompounds as thrombin inhibitors, anticoagulants and as antiinflammatoryagents.

Thrombin belongs to the group of serine proteases and plays a centralpart in the blood coagulation cascade as terminal enzyme. Both theintrinsic and the extrinsic coagulation cascade lead via a plurality ofamplifying stages to the production of thrombin from prothrombin.Thrombin-catalyzed cleavage of fibrinogen to fibrin then initiates bloodcoagulation and aggregation of platelets which, in turn, due to thebinding of platelet factor 3 and coagulation factor XIII, and a largenumber of highly active mediators, enhance thrombin formation.

The formation and action of thrombin are central events in thedevelopment of white, arterial, and of red, venous, thrombi and aretherefore potentially effective points of attack for drugs. Thrombininhibitors are, by contrast with heparin, able independently ofcofactors completely to inhibit simultaneously the effects of freethrombin and of that bound to platelets. They are able to prevent in theacute phase thromboembolic events after percutaneous transluminalcoronary angioplasty (PTCA) and lysis, and to act as anticoagulants inan extracorporeal circulation (heart-lung machine, hemodialysis). Theycan also be used generally for the prophylaxis of thrombosis, forexample after surgical operations.

It is known that synthetic arginine derivatives influence the enzymaticactivity of thrombin by interacting with the active serine residue ofthe protease thrombin. Peptides based on Phe-Pro-Arg in which theN-terminal amino acid is in the D form have proven particularlybeneficial. D-Phe-Pro-Arg-isopropyl ester is described as a competitivethrombin inhibitor (C. Mattson et al., Folia Haematol, 109, 43–51,1983). WO 94/29336, EP 0 601 459 and WO 95/23609 and WO 95/35309represent a further development in which the agmatine residue isreplaced by an arylamidine residue.

EP 0 672 658 describes not only thrombin inhibitors having an agmatineor benzamidine residue but also a thrombin inhibitor with anamidinothiophene (Example 65).

WO 98/06741 describes thrombin inhibitors with five-memberedheterocyclic amidines.

Although these compounds have a significant antithrombotic action, animprovement in their pharmacokinetic properties after oral or parenteraladministration is advantageous. It is desirable inter alia to influencethe following pharmacokinetic properties:

-   I. Improving the absorption from the gastrointestinal tract, aiming    at high bioavailability.-   II. Minimizing the inter- and intraindividual variability of the    bioavailability through a constant absorption basis.-   III. Achieving therapeutically relevant active levels which are as    constant as possible over the time course. In relation to the    therapeutic index, plasma concentrations which are as constant as    possible over the time course are indispensable, because excessive    fluctuations may lead to unwanted side effects. If the plasma    concentration of the active substance is too high, hemorrhages may    be expected, and if the concentration is too low there is an    increased risk of thrombus formation.-   IV. Prolonging the duration of action of the active substance:    Active substance means the pharmacologically active substance (drug)    in contrast to the substance (prodrug) which must first be converted    metabolically into the active substance.

A further advantage of prodrugs over drugs is that there are no highlocal concentrations of the drugs outside the target area. Moreover,when using less selective drugs, the side effects are minimised, sincee.g. in the gastrointestinal tract no further serine proteases areinhibited when the drug is essentially only produced after or during thegastrointestinal passage by metabolising the prodrug.

The aim of this invention is to improve the pharmacokinetic propertiesof the thrombin inhibitors mentioned in particular in WO 98/6741 throughsuitable prodrugs.

The invention relates to compounds of the formula I

in which A, B, D, E, G and K have the following meanings:

-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂—R¹OOC—CH(C₂H₅)—, C₁₋₄-alkyl-SO₂—(CH₂)₂₋₆—,    HO₃S—(CH₂)₂₋₆—, 5-te-trazyolyl-(CH₂)₁₋₆—, C₁₋₄-alkyl-O—(CH₂)₂₋₆—,    R²R³N—(CH₂)₂₋₆—, R²S(CH₂)₂₋₆—, R²R³NSO₂—(CH₂)₂₋₆—, HO—(CH₂)₂₋₆—,    R^(1a)S(O)C—CH₂—, R^(1a)O(S)C—CH₂—, R²R³N(O)C—CH₂—, R²R³N—O—CO—CH₂—,    R²N(OH)—CO—CH₂—, where R² and R³ are, independently of one another,    H, C₁–C₆-alkyl, C₃–C₈-cycloalkyl or C₃₋₈-cycloalkyl-C₁₋₃-alkyl- or    R² and R³ form together a C₄₋₆-alkylene chain,    in which-   R¹: is H—, C₁–C₆-alkyl, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl, C₁₀-tricycloalkyl, C₃–C₈-cycloalkyl,    C₃₋₈-cycloalkyl-C₁₋₃-alkyl-, pyranyl-, piperidinyl-, aryl- or    phenyl-C₁–C₄-alkyl-, it being possible for all the radicals    mentioned apart from H to carry optionally up to four identical or    different radicals selected from C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or    C₁–C₄-alkoxy radicals, or R¹ is 2-oxo-1,3-dioxol-4-ylmethyl which    may be substituted in position 5 by C₁–C₁₆-alkyl or aryl,-   R^(1a): is H—, C₁–C₁₆-alkyl, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl, C₁₀-tricycloalkyl, C₃–C₈-cycloalkyl,    C₃–C₈-cycloalkyl-C₁–C₃-alkyl, aryl- or phenyl-C₁–C₃-alkyl, it being    possible for all the radicals mentioned apart from H to carry    optionally up to three identical or different radicals selected from    C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or C₁–C₄-alkoxy radicals,    or-   R¹: R^(1b)—C(O)O—C(R^(1c))₂—, R^(1b)—(CO)NR²—C(R^(1c))₂—, where    R^(1b) can be C₁–C₄-alkyl, C₃–C₈-cycloalkyl-C₁–C₃-alkyl,    C₃–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₃–C₈-cycloalkyl-C₁–C₃-alkyloxy,    C₃–C₈-cycloalkoxy, aryl or phenyl-C₁–C₆-alkyl, the two R^(1c)    radicals are, independently of one another, H, CH₃ or C₂H₅, and R²    has the same meaning as above, or R²OOC—C₁–C₆-alkyl,    R²R³N(O)C—C₁–C₆-alkyl, R²R³N—C₂–C₆-alkyl, and in which R² and R³    have the same meanings as above or, if R¹ is R²R³N(O)C—C₁–C₆-alkyl,    R² and R³ together form a C₄–C₆-alkyl chain,

in which

-   p is 0, 1,-   R⁴: is H—, R⁹OOC— with R⁹═C₁₋₁₆-alkyl, C₃₋₈-cycloalkyl-, phenyl-,    phenyl-C₁₋₄-alkyl-, R¹⁰C(O)—O—CH₂—, R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰    can be C₁–C₄-alkyl, phenyl, benzyl, C₃–C₈-cycloalkyl or    cyclohexyl-CH₂—,-   R⁵ is H—,-   R⁶ is H—, C₁₋₈-alkyl, C₇–C₁₂-bicycloalkyl or C₁₀-tricycloalkyl,    phenyl which may carry up to three identical or different radicals    from the group of C₁₋₄-alkyl, CF₃—, C₁₋₄-alkoxy, F— or Cl—, or    C₃₋₈-cycloalkyl which may carry up to four identical or different    C₁₋₄-alkyl radicals, or where one or two C—C single bonds in the    ring can be replaced by a C═C double bond, or a phenyl ring can be    fused on,-   R⁷ is H—, C₁₋₈-alkyl, phenyl which may carry up to three identical    or different radicals from the group of C₁₋₄-alkyl, CF₃—,    C₁₋₄-alkoxy, F— or Cl—, or C₃₋₈-cycloalkyl which may carry up to    four identical or different C₁₋₄-alkyl radicals,-   R⁸ is H—, CH₃—,

with

-   X=S, O-   Y=CH, C—CH₃, C—Cl, C—CF₃ and-   Z=CH, C—CH₃, C—Cl, C—CF₃-   or X=S, O Y=N Z=CH, C—CH₃, C—CF₃-   or X=S, O Y=CH, C—CH₃, C—CF₃ Z=N,

with

-   X=S, O-   Y=CH, C—CH₃ and C—CF₃-   Z=CH, C—CH₃, C—Cl and C—CF₃-   or X=O Y=N Z=CH, C—CH₃, C—CF₃-   or X=O, S Y=CH, C—CH₃, C—CF₃ Z=N-   G: —H, —OH, —OR¹⁸, —OC(O)R¹⁹, —C(O)OR²⁰, —SR¹⁸, —C(S)SR²⁰,    in which-   R¹⁸: is —C₁₋₈-alkyl, —C₁–C₃-alkyl-C₃–C₈-cycloalkyl, -aryl or    —C₁–C₆-alkylphenyl, each of which may carry optionally up to three    C₁–C₄-alkyl, CF₃, F, Cl, NO₂ or C₁–C₄-alkoxy radicals-   R¹⁹: is —C₁₋₃-alkyl, -phenyl,-   R²⁰: is —C₁₋₈-alkyl, —CH₂CCl₃, —C₁–C₃-alkyl-C₃–C₈-cycloalkyl,    —C₃–C₈-cycloalkyl, -phenyl or C₁–C₃-alkylphenyl, each of which may    carry optionally up to three identical or different radicals    selected from the group of C₁–C₄-alkyl, CF₃, F, Cl, NO₂ or    C₁–C₄-alkoxy radicals, or CH₂O—C(O)R^(10a), —CH(CH₃)O—C(O)R^(10a),    where R^(10a) can be C₁–C₁₀-alkyl, -phenyl, benzyl,    —C₃–C₈-cycloalkyl or —CH₂-cyclohexyl, or    —C(R^(10b))₂—CH₂—O—(O)C—R^(10c), where the two R^(10b) radicals can    be, independently of one another, H, CH₃ or ethyl, and R^(10c) is    —C₁–C₃-alkyl-C₃–C₈-cycloalkyl, —C₃–C₈-cycloalkyl or —C₁–C₄-alkyl,-   K: H,    or G and K together form a —C(O)O—, —C(O)S—, C(S)S— or —C(S)O—    group,    the configurational isomers thereof and the salts thereof with    physiologically tolerated acids,    where the following applies, with retention of the meanings of D:    (i)    when E is II or III, and G and K are H, then A and B have the    following meanings:-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—, R¹OOC—CH(C₂H₅)—,    R¹OOC—C(CH₃)₂—, R^(1a)S(O)C—CH₂—, R^(1a)O(S)C—CH₂—, R²R³N(O)C—CH₂—,    R²R³N—CO—CH₂—, R²N(OH)—CO—CH₂—, C₁₋₄-alkyl-SO₂—(CH₂)₂₋₆—,    HO₃S—(CH₂)₂₋₆—, 5-tetrazyolyl-(CH₂)₁₋₆—, C₁₋₄-alkyl-O—(C₂)₂₋₆—,    R²R³N—(CH₂)₂₋₆—, R²S(CH₂)₂₋₆—, R²R³NSO₂—(CH₂)₂₋₆—, where R² and R³    are, independently of one another, H or C₁–C₆-alkyl, or    C₃₋₈-cycloalkyl, or R² and R³ form together a C₄₋₆-alkyl chain,    in which-   R¹: is C₇–C₁₆-alkyl-, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl-, C₁₀-tricycloalkyl-, C₃–C₈-cycloalkyl-,    C₃–C₈-cycloalkyl-C₁–C₃-alkyl-, pyranyl-, piperidinyl-, it being    possible for all the radicals mentioned to carry optionally up to    four C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or C₁–C₄-alkoxy radicals, or    R¹ is 2-oxo-1,3-dioxol-2-ylmethyl which may be substituted in    position 5 by C₁–C₁₆-alkyl or aryl,-   R^(1a): is H—, C₁–C₁₆-alkyl, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₃–C₈-cycloalkyl, C₃–C₈-cycloalkyl-C₁–C₃-alkyl, aryl or    phenyl-C₁–C₃-alkyl, it being possible for all the radicals mentioned    apart from H to carry optionally up to three C₁–C₄-alkyl, CF₃, F,    Cl, NO₂, HO or C₁–C₄-alkoxy radicals, or-   R¹: is R^(1b)—C(O)O—C(R^(1c))₂—, R^(1b)—C(O)NR²—C(R^(1c))₂—, where    R^(1b) can be C₁–C₄-alkyl, C₃–C₈-cycloalkyl-C₁–C₃-alkyl,    C₃–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₃–C₈-cycloalkyl-C₁–C₃-alkyloxy,    C₃–C₈-cycloalkoxy, aryl or phenyl-C₁–C₆-alkyl, the two R^(1c)    radicals are, independently of one another, H, CH₃ or C₂H₅, or    R²OOC—C₁–C₆-alkyl, R²R³N(O)C—C₁–C₆-alkyl, R²R³N—C₂–C₆-alkyl, where    R² and R³ have the same meanings as above or, if R¹ is    R²R³N(O)C—C₁–C₆-alkyl, R² and R³ together form a C₄–C₆-alkyl chain,

in which

-   p is 0, 1,-   R⁴ is H—, R⁹OOC— with R⁹=C₁₋₁₆-alkyl, phenyl-C₁–C₄-alkyl,    R¹⁰C(O)—O—CH₂—, R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰ can be C₁–C₄-alkyl,    phenyl, benzyl, C₃–C₈-cycloalkyl or cyclohexyl-CH₂—,-   and R⁵, R⁶, R⁷ and R⁸ have the same meanings as above;    (ii)    when E is II or III, and G and K are H, then A and B have the    following meanings    -   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—, R¹OOC—CH(C₂H₅)—,        HO—CH₂—CH₂—,        in which-   R¹: is H—, C₁–C₉-alkyl, aryl or phenyl-C₁–C₃-alkyl, it being    possible for all the radicals mentioned apart from H to carry    optionally up to three identical or different radicals selected from    C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or C₁–C₄-alkoxy radicals,

in which

-   p is 0, 1,-   R⁴ is R⁹OOC— with R⁹=C₇₋₁₆-alkyl, R¹⁰C(O)—O—CH₂—,    R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰ can be C₁–C₄-alkyl, phenyl, benzyl,    C₃–C₈-cycloalkyl or cyclohexyl-CH₂—,-   and R⁵, R⁶, R⁷ and R⁸ have the same meanings as above;    (iii)    when E is II or III, and G is —OH, —OR¹⁸, —OC(O)R¹⁹, C(O)OR²⁰,    —SR¹⁸, —C(S)SR²⁰, where R¹⁸, R¹⁹ and R²⁰ have the same meanings as    above, and K is H, or G and K together form a C(O)O—, —C(O)S—,    —C(S)S— or —C(S)O— group, then A and B have the following meanings:-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂——R¹OOC—CH(C₂H₅)—, C₁₋₄-alkyl-SO₂—(CH₂)₂₋₆—, HO₃S—    (CH₂)₂₋₆—, 5-te-trazyolyl-(CH₂)₁₋₆—, C₁₋₄-alkyl-O—(CH₂)₂₋₆—,    R²R³N—(CH₂)₂₋₆—, R²S(CH₂)₂₋₆—, R²R³NSO₂—(CH₂)₂₋₆—, HO—(CH₂)₂₋₆—,    R^(1a)S(O)C—CH₂—, R^(1a)O(S)C—CH₂—, R²R³N(O)C—CH₂—, R²R³N—O—CO—CH₂—,    R²N(OH)—CO—CH₂—, where R² and R³ are, independently of one another,    H, C₁–C₆-alkyl, or C₃–C₈-cycloalkyl or R² and R³ form together a    C₄₋₆-alkyl chain,    in which-   R¹: is H—, C₃–C₁₆-alkyl-, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl-, C₁₀-tricycloalkyl-, C₃–C₈-cycloalkyl-,    C₃–C₈-cycloalkyl-C₁–C₃-alkyl-, pyranyl-, piperidinyl-, aryl-, or    phenyl-C₁–C₃-alkyl, it being possible for all the radicals mentioned    apart from H to carry optionally up to four identical or different    radicals selected from C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or    C₁–C₄-alkoxy radicals, or R¹ is 2-oxo-1,3-dioxol-4-ylmethyl which    may be substituted in position 5 by C₁–C₁₆-alkyl or aryl,-   R^(1a): is H—, C₂–C₁₆-alkyl, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇₋₁₂-bicycloalkyl, C₁₀-tricycloalkyl, C₃–C₈-cycloalkyl,    C₃–C₈-cycloalkyl-C₁–C₃-alkyl, aryl or phenyl-C₁–C₃-alkyl, it being    possible for all the radicals mentioned apart from H to carry    optionally up to three identical or different radicals selected from    C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or C₁–C₄-alkoxy radicals,    or-   R¹: is R^(1b)—C(O)O—C(R^(1c))₂—, R^(1b)—C(O)NR²—C(R^(1c))₂—, where    R^(1b) can be C₁–C₄-alkyl, C₃–C₈-cycloalkyl-C₁–C₃-alkyl,    C₃–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₃–C₈-cycloalkyl-C₁–C₃-alkyloxy,    C₃–C₈-cycloalkoxy, aryl or phenyl-C₁–C₆-alkyl, the two R^(1c)    radicals are, independently of one another, H, CH₃ or C₂H₅, and R²    has the same meaning as above, or R²OOC—C₁–C₆-alkyl,    R²R³N(O)C—C₁–C₆-alkyl, R²R³N—C₂–C₆-alkyl, and in which R² and R³    have the same meanings as above or, if R¹ is R²R³N(O)C—C₁–C₆-alkyl,    R² and R³ together form a C₄–C₆-alkyl chain,

in which

-   p is 0, 1,-   R⁴: is H—, R⁹OOC— with R⁹=C₁₋₃-alkyl, C₃₋₈-cycloalkyl-, phenyl-,    phenyl-C₁₋₄-alkyl-, R¹⁰C(O)—O—CH₂—, R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰    can be C₁–C₄-alkyl, phenyl, benzyl, cyclohexyl or cyclohexyl-CH₂—,    and-   R⁵, R⁶, R⁷ and R⁸ have the same meanings as above;    (iv)    when E is IV, V or VI, and G is H or OH and K is H, then A and B    have the following meanings:-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂—R¹OOC—CH(C₂H₅)—, R^(1a)S(O)C—CH₂—, R^(1a)O(S)C—CH₂—,    R²R³N(O)C—CH₂—, R²R³N—O—CO—CH₂—, R²N(OH)—CO—CH₂—, where R² and R³    are, independently of one another, H, C₁–C₆-alkyl, C₃–C₈-cycloalkyl    or R² and R³ form together a C₄₋₆-alkyl chain,    in which-   R¹: is C₇–C₁₆-alkyl, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl, C₁₀-tricycloalkyl, C₃–C₈-cycloalkyl,    C₃–C₈-cycloalkyl-C₁–C₃-alkyl, it being possible for all the radicals    mentioned apart from H to carry optionally up to three identical or    different radicals selected from C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or    C₁–C₄-alkoxy radicals, or 2-oxo-1,3-dioxol-4-yl-methyl- which may be    substituted in position 5 by C₁₋₆-alkyl or aryl,-   R^(1a): is H—, C₁–C₁₆-alkyl, C₇–C₁₂-bicycloalkyl, C₁₀-tricycloalkyl,    C₃–C₈-cycloalkyl, C₃–C₈-cycloalkyl-C₁–C₃-alkyl, aryl or    phenyl-C₁–C₃-alkyl, it being possible for all the radicals mentioned    apart from H to carry optionally up to three identical or different    radicals selected from C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or    C₁–C₄-alkoxy radicals,    or-   R¹: is R^(1b)—C(O)O—C(R^(1c))₂—, R^(1b)—C(O)NR²—C(R^(1c))₂—, where    R^(1b) can be C₁–C₄-alkyl, C₃–C₈-cycloalkyl-C₁–C₃-alkyl,    C₃–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₃–C₈-cycloalkyl-C₁–C₃-alkyloxy,    C₃–C₈-cycloalkoxy, aryl or phenyl-C₁–C₆-alkyl, the two R^(1c)    radicals are, independently of one another, H, CH₃ or C₂H₅, and R²    has the same meaning as above, or R²OOC—C₁–C₆-alkyl,    R²R³N(O)C—C₁–C₆-alkyl, R²R³N—C₂–C₆-alkyl,    and in which R² and R³ have the same meanings as above or, if R¹ is    R²R³N(O)C—C₁–C₆-alkyl, R² and R³ together form a C₄–C₆-alkyl chain,

in which

-   p is 0, 1,-   R⁴ is H—, R⁹OOC— with R⁹=C₁₋₁₆-alkyl, phenyl-C₁–C₄-alkyl,    R¹⁰C(O)—O—CH₂—, R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰ can be C₁–C₄-alkyl,    phenyl, benzyl, C₃–C₈-cycloalkyl or cyclohexyl-CH₂—,    and-   R⁵, R⁶, R⁷ and R⁸ have the same meanings as above;    (v)    when E is IV, V or VI, and G is H or OH and K is H, then A and B    have the following meanings:-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂—R¹OOC—CH(C₂H₅)—, HO—(CH₂)₂₋₆—,    in which-   R¹: is H—, C₁–C₉-alkyl, aryl or phenyl-C₁–C₃-alkyl, it being    possible for all the radicals mentioned apart from H to carry    optionally up to three C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or    C₁–C₄-alkoxy radicals,

in which

-   p is 0, 1,-   R⁴ is R⁹OOC— with R⁹=C₇₋₁₆-alkyl, R¹⁰C(O)—O—CH₂—,    R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰ can be C₁–C₄-alkyl, phenyl, benzyl,    C₃–C₈-cycloalkyl or cyclohexyl-CH₂—,    and-   R⁵, R⁶, R⁷ and R⁸ have the same meanings as above;    (vi)    when E is IV, V or VI, and G is —OR¹⁸, —OC(O)R¹⁹, C(O)OR²⁰, —SR¹⁸,    —C(S)SR²⁰, where R¹⁸, R¹⁹ and R²⁰ have the same meanings as above,    and K is H, or G and K together form a —C(O)O—, —C(O)S—, C(S)S— or    —C(S)O— group, then A and B have the following meanings:-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂—R¹OOC—CH(C₂H₅)—, HO—CH₂—CH₂—, R^(1a)S(O)C—CH₂—,    R^(1a)O(S)C—CH₂—, R²R³N(O)C—CH₂—, R²R³N—O—CO—CH₂—, R²N(OH)—CO—CH₂—,    where R² and R³ are, independently of one another, H, C₁–C₆-alkyl,    C₃–C₈-cycloalkyl or R² and R³ form together a C₄₋₆-alkyl chain,    in which-   R¹: is H—, C₁–C₁₆-alkyl-, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl-, C₁₀-tricycloalkyl-, C₃–C₈-cycloalkyl-,    C₃–C₈-cycloalkyl-C₁–C₃-alkyl-, pyranyl-, piperidinyl-, aryl-, or    phenyl-C₁–C₃-alkyl, it being possible for all the radicals mentioned    apart from H to carry optionally up to three identical or different    radicals selected from C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or    C₁–C₄-alkoxy radicals, or R¹ is 2-oxo-1,3-dioxol-4-ylmethyl which    may be substituted in position 5 by C₁–C₁₆-alkyl or aryl,-   R^(1a): is H—, C₁–C₁₆-alkyl, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl, C₁₀-tricycloalkyl, C₃–C₈-cycloalkyl,    C₃–C₈-cycloalkyl-C₁–C₃-alkyl, aryl or phenyl-C₁–C₃-alkyl, it being    possible for all the radicals mentioned apart from H to carry    optionally up to three identical or different radicals selected from    C₁–C₄-alkyl, CF₃, F, Cl, NO₂, HO or C₁–C₄-alkoxy radicals,    or-   R¹: is R^(1b)—C(O)O—C(R^(1c))₂—, R^(1b)—C(O)NR²—C(R^(1c))₂—, where    R^(1b) can be C₁–C₄-alkyl, C₃–C₈-cycloalkyl-C₁–C₃-alkyl,    C₃–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₃–C₈-cycloalkyl-C₁–C₃-alkyloxy,    C₃–C₈-cycloalkoxy, aryl or phenyl-C₁–C₆-alkyl, the two R^(1c)    radicals are, independently of one another, H, CH₃ or C₂H₅, or    R²OOC—C₁–C₆-alkyl, R²R³N(O)C—C₁–C₆-alkyl, R²R³N—C₂–C₆-alkyl, and in    which R² and R³ have the same meanings as above or, if R¹ is    R²R³N(O)C—C₁–C₆-alkyl, R² and R³ together form a C₄–C₆-alkyl chain,

in which

-   p is 0, 1,-   R⁴: is H—, R⁹OOC— with R⁹=C₁₋₁₆-alkyl, C₃₋₈-cycloalkyl-, phenyl-,    phenyl-C₁₋₄-alkyl-, R¹⁰C(O)—O—CH₂—, R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰    can be C₁–C₄-alkyl, phenyl, benzyl, C₃–C₈-cycloalkyl or    cyclohexyl-CH₂—,    and-   R⁵, R⁶, R⁷ and R⁸ have the same meanings as above;    and the physiologically tolerated salts thereof.

The amino acid derivatives represented by B are preferably in theD-configuration, the amino acid derivatives represented by Ein theL-configuration.

The aforementioned compounds belong to three groups of substances:

-   -   The first group comprises prodrugs of thrombin inhibitors (e.g.        G equals —OH, —OR¹⁸, —COOR²⁰ etc.) which is a substance to only        a negligible antithromotic effect, which, however, are converted        in the organism into the active substance (G equals H). These        are compounds of groups (iii) and (vi), partially also of        groups (iv) and (v). The advantage of the prodrugs lies in their        improved pharmacokinetic and pharmacodynamic behaviour in the        organism.    -   The second group comprises prodrugs of thrombin inhibitors which        show already as a prodrug a thrombin-inhibiting effect (e.g. A        equals R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)— etc. in        combination with G equals —H). The effective substance formed in        the organism (drug; A equals HOOC—CH₂—, HOOC—CH₂—CH₂—,        HOOC—CH(CH₃)— etc., G equals —H) shows also a        thrombin-inhibiting effect. These are in part compounds of        groups (i), (ii), (iv) and (v). The advantage of these prodrugs        lies also in their improved pharmacokinetic and pharmacodynamic        behaviour in the organism. Compounds wherein G equals —OH,        —OR¹⁸, —COOR²⁰ etc., and simultaneously A equals R¹OOC—CH₂—,        R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)— etc. are double prodrugs which        are converted in the organism into the respective drug (G equals        —H, A equals HOOC—CH₂— etc.) by converting both prodrug groups.    -   The third group comprises thromin inhibitors which per se show        the antithrombotic effect (e.g. A equals        C₁₋₄-alkyl-SO₂—(CH₂)₂₋₆—, HO₃—S—(CH₂)₂₋₆—,        5-tetrazolyl-(CH₂)₁₋₆—, C₁₋₄-alkyl-O—(CH₂)₂₋₆—, R²R³N—(CH₂)₂₋₆—,        R²S—(CH₂)²⁻⁶—, R²R³NSO₂—(CH₂)₂₋₆—, in combination with G equals        —H). Such compounds are included in group (i).    -   Preferred compound of the formula I are those in which A, B, D,        E, G and K have the following meanings:

-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂—R^(1a)S(O)C—CH₂—, R^(1a)O(S)C—CH₂—, R²R³N(O)C—CH₂—,    R²R³N—O—CO—CH₂—, R²N(OH)—CO—CH₂—, C₁₋₄-alkyl-SO₂—(CH₂)₂₋₆—,    HO₃S—(CH₂)₂₋₆—, 5-te-trazyolyl-(CH₂)₁₋₆—, C₁₋₄-alkyl-O—(CH₂)₂₋₆—,    R²R³N—(CH₂)₂₋₆—, R²S(CH₂)₂₋₆—, R²R³NSO₂—(CH₂)₂₋₆—, where R² and R³    are, independently of one another, H, C₁–C₆-alkyl, C₃–C₈-cycloalkyl    or R² and R³ form together a butylene or pentylen chain,    in which

-   R¹: is H—, C₁–C₁₆-alkyl-, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₇–C₁₂-bicycloalkyl-, C₁₀-tricycloalkyl-, C₃–C₈-cycloalkyl-,    C₅–C₈-cycloalkyl-C₁–C₃-alkyl-, pyranyl-, piperidinyl-, aryl-, or    phenyl-C₁–C₃-alkyl, it being possible for all the radicals mentioned    apart from H to carry optionally up to four identical or different    radicals selected from CH₃, CF₃, F, Cl, HO or methoxy radicals, or    R¹ is 2-oxo-1,3-dioxol-4-ylmethyl which may be substituted in    position 5 by C₁–C₆-alkyl or aryl,

-   R^(1a): is H—, C₁–C₁₆-alkyl, C₇–C₁₂-bicycloalkyl, C₁₀-tricycloalkyl,    C₅–C₈-cycloalkyl, C₅–C₈-cycloalkyl-C₁–C₃-alkyl, aryl or    phenyl-C₁–C₃-alkyl, it being possible for all the radicals mentioned    apart from H to carry optionally up to four identical of different    radicals selected from CH₃, CF₃, F, Cl, HO or methoxy radicals,    or    -   R¹: is R^(1b)—C(O)O—C(R^(1c))₂—, R^(1b)—C(O)NR²—C(R^(1c))₂—,        where R^(1b) can be C₁–C₄-alkyl, C₅–C₈-Cycloalkyl-C₁–C₃-alkyl,        C₅–C₈-cycloalkyl, C₁–C₄-alkyloxy,        C₅–C₈-cycloalkyl-C₁–C₃-alkyloxy, C₅–C₈-cycloalkoxy, aryl or        phenyl-C₁–C₃-alkyl, the two R^(1c) radicals are, independently        of one another, H, CH₃ or C₂H₅, or R²OOC—C₁–C₆-alkyl,        R²R³N(O)C—C₁–C₆-alkyl, R²R³N—C₂–C₆-alkyl, and in which R² and R³        have the same meanings as above or, if R¹ is        R²R³N(O)C—C₁–C₆-alkyl, R² and R³ together form a butylene or        pentylene chain,

in which

-   p is 0, 1,-   R⁴: is H—, R⁹OOC— with R⁹=C₁₋₁₆-alkyl, C₃₋₈-cycloalkyl-,    R¹⁰C(O)—O—CH₂—, R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰ can be C₁–C₄-alkyl,    phenyl, benzyl, C₅–C₈-cycloalkyl or cyclohexyl-CH₂—,-   R⁵ is H—,-   R⁶ is C₁₋₈-alkyl, C₅₋₈-cycloalkyl, which may carry up to four methyl    radicals, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, norbornyl,    adamantyl, indanyl, decalinyl,-   R⁷ is H,-   R⁸ is H,

in which

-   R¹⁴: is H, CH₃, Cl-   R¹⁵: is H, CF₃,-   R¹⁷: is H, CH₃, CF₃,-   G: H, —OH, —OR¹⁸, —OC(O)R¹⁹, —C(O)OR²⁰,    in which-   R¹⁸: is —C₁₋₈-alkyl, —C₁–C₃-alkyl-C₃–C₈-cycloalkyl,    —C₁–C₃-alkylphenyl which may carry optionally up to three CH₃, CF₃,    F, Cl or methoxy radicals,-   R¹⁹: is —C₁₋₃-alkyl,-   R²⁰: is —C₁₋₈-alkyl, —CH₂CCl₃, —C₁–C₃-alkyl-C₅–C₈-cycloalkyl,    —C₅–C₈-cycloalkyl, -phenyl or —C₁–C₃-alkylphenyl, each of which may    carry optionally up to three CH₃, CF₃, F, Cl or methoxy radicals,    —CH₂O—C(O)R^(10a), —CH(CH₃)O—C(O)R^(10a), where R^(10a) can be    —C₁–C₈-alkyl, -phenyl, -benzyl, —C₅–C₈-cycloalkyl or    —CH₂-cyclohexyl, or —C(R^(10b))₂—CH₂—O—(O)CR¹⁰, where the R^(10b)    radicals can be, independently of one another, H or CH₃, and R^(10c)    is —C₁–C₃-alkyl-C₅–C₈-cycloalkyl, —C₅–C₈-cycloalkyl or —C₁–C₄-alkyl,    or-   K is H or G and K together form a —C(O)O— or —C(O)S— group.

Particularly preferred compounds of the formula I are those in which A,B, D, E, G and K have the following meanings:

-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂—R²R³N(O)C—CH₂—, C₁₋₄-alkyl-SO₂—(CH₂)₂₋₆—,    5-tetrazyolyl-(CH₂)₁₋₆—, C₁₋₄-alkyl (CH₂)₂₋₆—, R²R³N—(CH₂)₂₋₆—,    R²S(CH₂)₂₋₆—, —R²R³NSO₂—(CH₂)₂₋₆—, where R² and R³ are independently    of one another, H or C₁–C₄-alkyl    in which-   R¹: is H—, C₁–C₁₆-alkyl, H₃C—[O—CH₂—CH₂]_(q) (q=1–4),    C₁₀-tricycloalkyl, C₅–C₈-cycloalkyl, C₅–C₈-cycloalkyl-C₁–C₃-alkyl,    phenyl-C₁–C₃-alkyl, it being possible for all the radicals mentioned    apart from H to carry optionally up to three identical or different    radicals selected from CH₃, CF₃, F, Cl, HO or methoxy radicals, or    R¹ is 2-oxo-1,3-dioxol-4-ylmethyl which may be substituted in    position 5 by C₁–C₃-alkyl or aryl,    or-   R¹: is R^(1b)—C(O)O—C(R^(1c))₂—, where R^(1b) can be C₁–C₄-alkyl,    C₅–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₅–C₈-cycloalkyloxy or    phenyl-C₁–C₃-alkyl, the two R^(1c) radicals are, independently of    one another, H or CH₃, or R²OOC—C₁–C₆-alkyl, R²R³N(O)C—C₁–C₆-alkyl,    R²R³N—C₂–C₆-alkyl, and in which R² and R³ have the same meanings as    above or, if R¹ is R²R³N(O)C—C₁–C₆-alkyl, R² and R³ together form a    butylene or pentylene chain,

in which

-   p is 0, 1,-   R⁴ is H—, R⁹OOC— with R⁹=C₁₋₁₆-alkyl, R¹⁰C(O)—O—CH₂—,    R¹⁰C(O)—O—CH(CH₃)—, where R¹⁰ can be C₁–C₄-alkyl,-   R⁵ is H—,-   R⁶ is C₁₋₈-alkyl, cyclopentyl, cyclohexyl, cycloheptyl,    bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, norbornyl, adamantyl,    indanyl, decalinyl,-   R⁷ is H,-   R⁸ is H,

in which

-   R¹⁴: is H, CH₃, Cl-   G: H, —OH, —OR¹⁸, —C(O)OR²⁰,    in which-   R¹⁸: is —C₁₋₈-alkyl, —C₁–C₃-alkyl-C₃–C₈-cycloalkyl,    —C₁–C₃-alkylphenyl which may carry optionally up to three CH₃, CF₃,    F, Cl, or methoxy radicals,-   R²⁰: is —C₁₋₈-alkyl, —C₁–C₃-alkyl-C₅–C₈-cycloalkyl,    —C₅–C₈-cycloalkyl or —C₁–C₃-alkylphenyl which may carry optionally    up to three CH₃, CF₃, F, Cl or methoxy radicals, or    —CH₂O—C(O)R^(10a), —CH(CH₃)O—C(O)R^(10a), where R^(10a) can be    —C₁–C₄-alkyl, -benzyl, —C₅–C₈-cycloalkyl or —CH₂-cyclohexyl,-   K is H,    or G and K together form a —C(O)O— or —C(O)S— group.    -   Very particularly preferred are compounds of the formula I as        claimed in claim 1, where A, B, D, E, G and K have the following        meanings-   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,    R¹OOC—C(CH₃)₂—C₁₋₄-alkyl-SO₂—(CH₂)₂₋₆—,    5-tetrazyolyl-(CH₂)₁₋₆—C₁₋₄-alkyl-O—(CH₂)₂₋₆—, H₂N—(CH₂)₂₋₃—,    CH₃—NH—(CH₂)₂₋₃—, (CH₃)₂N—(CH₂)₂₋₃—, H₂NSO₂—(CH₂)₂₋₄—,    CH₃—NHSO₂—(CH₂)₂₋₄—,    in which-   R¹: is H—, C₁–C₈-alkyl-, C₅–C₈-cycloalkyl-,    C₅–C₈-cycloalkyl-C₁–C₃-alkyl-, it being possible for all the    radicals mentioned apart from H to carry optionally up to four    identical or different radicals selected from CH₃, CF₃, F, Cl, or    methoxy radicals, or R¹ is 2-oxo-1,3-dioxo-4-yl-methyl which may be    substituted in the 5-position by C₁–C₃-alkyl or aryl,    or-   R¹: is R^(1b)—C(O)O—CH₂—, R^(1b)—C(O)O—CH(CH₃)—, where R^(1b) can be    C₁–C₄-alkyl-, C₅–C₈-cycloalkyl-, C₁–C₄-alkyloxy- or    C₅–C₈-cycloalkyloxy-,

in which

-   p is 0,1,-   R⁴ is H—,-   R⁵ is H—,-   R⁶ is cyclopentyl, cyclohexyl, cycloheptyl,-   R⁷ is H,-   R⁸ is H,

in which

-   R¹⁴: is H, CH₃, Cl,-   G: is —OH, —C(O)OR²⁰,    in which-   R²⁰: is —C₁₋₈-alkyl, —C₁–C₃-alkyl-C₅–C₈-cycloalkyl,-   K is H.    -   Very preferred compounds of the formula I are those in which A,        B, D, E, G, and K have the following meanings:    -   A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—, R¹OOC—C(CH₃)₂—    -   in which    -   R¹: is C₁–C₈-alkyl-, C₅–C₈-cycloalkyl-,        C₅–C₈-cycloalkyl-CH₂-alkyl-, it being possible for all the        radicals mentioned to carry optionally up to four identical or        different radicals selected from CH₃ or methoxy radicals,

-   -   in which    -   p is 0,1,    -   R⁴ is H—,    -   R⁵ is H—,    -   R⁶ is cyclohexyl,    -   R⁷ is H,    -   R⁸ is H,

-   G: is —OH,-   K is H.    -   The following substances are very particularly preferred:

1. CH₃OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 2.EtOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 3.nPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 4.iPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 5.nBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 6.tBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 7.iBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 8.nPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 9.iPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 10.neoPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 11.nHexOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 12.cHex-OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 13.nHeptOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 14.nOctOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 15.cOctOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 16.BnOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 17.AdaOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 18.AdaOOC—CH₂—(D)-Chg-Dep-NH—CH₂-5-[2-am-(OH)]-thioph 19.cHex-CH₂OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 20.AdaOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 21.cHex-CH₂OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 22.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 23.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 24.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 25.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 26.CH₃OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 27.CH₃OOC—CH₂—(D)-Cha-Dep-NH—CH₂-5-[2-am-(OH)]-thioph 28.EtOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 29.nPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 30.nPrOOC—CH₂—(D)-Cha-Dep-NH—CH₂-5-[2-am-(OH)]-thioph 31.iPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 32.nBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 33.tBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 34.iBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 35.nPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 36.iPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 37.neoPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 38.nHexOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 39.cHex-OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 40.nHeptOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 41.nOctOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 42.cOctOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 43.BnOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 44.AdaOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 45.cHex-CH₂OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 46.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 47.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 48.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 49.AdaOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 50.cHex-CH₂OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 51.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 52.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 53.CH₃OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OMe)]-thioph 54.CH₃OOC—CH₂—(D)-Cha-Dep-NH—CH₂-5-[2-am-(OMe)]-thioph 55.EtOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OMe)]-thioph 56.nPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OMe)]-thioph 57.CH₃OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 58.nPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 59.iPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 60.nBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 61.nBuOOC—CH₂—(D)-Chg-Dep-NH—CH₂-5-[3-am-(OH)]-thioph 62.iBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 63.nPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 64.iPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 65.neoPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 66.nHeptOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 67.nOctOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 68.nOctOOC—CH₂—(D)-Chg-Dep-NH—CH₂-5-[3-am-(OH)]-thioph 69.cOctOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 70.BnOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 71.AdaOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 72.cHex-CH₂OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 73.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 74.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 75.AdaOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 76.cHex-CH₂OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 77.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 78.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 79.EtOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OMe)]-thioph 80.tBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OMe)]-thioph 81.CH₃OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 82.CH₃OOC—CH₂—(D)-Cha-Dep-NH—CH₂-5-[3-am-(OH)]-thioph 83.EtOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 84.nPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 85.iPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 86.nBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 87.tBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 88.iBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 89.nPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 90.nPentOOC—CH₂—(D)-Cha-Dep-NH—CH₂-5-[3-am-(OH)]-thioph 91.iPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 92.neoPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 93.nHexOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 94.cHex-OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 95.nHeptOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 96.nOctOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 97.cOctOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 98.BnOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 99.BnOOC—CH₂—(D)-Cha-Dep-NH—CH₂-5-[3-am-(OH)]-thioph 100.AdaOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 101.cHex-CH₂OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 102.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 103.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 104.AdaOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 105.cHex-CH₂OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 106.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 107.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 108.CH₃OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 109.EtOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 110.EtOOC—CH₂—(D)-Chg-Dep-NH—CH₂-2-[4-am-(OH)]-thiaz 111.nPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 112.iPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 113.nBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 114.tBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 115.tBuOOC—CH₂—(D)-Chg-Dep-NH—CH₂-2-[4-am-(OH)]-thiaz 116.iBuOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 117.nPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 118.iPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 119.nHexOOC—CH₂—(D)-Chg-Dep-NH—CH₂-2-[4-am-(OH)]-thiaz 120.neoPentOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 121.nHexOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 122.cHex-OC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 123.nHeptOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 124.nOctOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 125.cOctOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 126.BnOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 127.AdaOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 128.cHex-CH₂OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 129.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 130.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 131.AdaOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(H)]-thiaz 132.cHex-CH₂OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(H)]-thiaz 133.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(H)]-thiaz 134.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(H)]-thiaz 135.CH₃OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 136.nPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 137.nPrOOC—CH₂—(D)-Cha-Dep-NH—CH₂-2-[4-am-(OH)]-thiaz 138.nBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 139.iBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 140.nPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 141.nPentOOC—CH₂—(D)-Cha-Dep-NH—CH₂-2-[4-am-(OH)]-thiaz 142.iPentOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 143.nHeptOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 144.nOctOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 145.cOctOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 146.BnOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 147.BnOOC—CH₂—(D)-Cha-Dep-NH—CH₂-2-[4-am-(OH)]-thiaz 148.cHex-CH₂OOC—CH₂—(D)-Cha-Dep-NH—CH₂-2-[4-am-(H)]-thiaz 149.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Dep-NH—CH₂-2-[4-am-(H)]-thiaz 150.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Cha-Dep-NH—CH₂-2-[4-am-(H)]-thiaz 151.CH₃OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OMe)]-thiaz 152.nPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OMe)]-thiaz 153.EtOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OMe)]-thiaz 154.nBuOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OMe)]-thiaz 155.HOOC—CH₂—N—(CO₂CH₂ ^(c)Hex)—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(H)]-thiaz 156.HOOC—CH₂—N—(CO₂ ^(c)Oct)-(D)-Cha-Pyr-NH—CH₂-2-[4-am-(H)]-thiaz 157.HOOC—CH₂—N—(CO₂ ^(c)Hex)-(D)-Cha-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 158.HOOC—CH₂—N—(CO₂CH₂ ^(c)Hex)-(D)-Cha-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 159.HOOC—CH₂—N—(CO₂ ^(c)Oct)-(D)-Cha-Pyr-NH—CH₂-5-[2-am-(H)]-thioph 160.HOOC—CH₂—N—(CO₂ ^(c)Hex)-(D)-Chg-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 161.HOOC—CH₂—N—(CO₂CH₂ ^(c)Hex)-(D)-Chg-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 162.HOOC—CH₂—N—(CO₂ ^(c)Oct)-(D)-Chg-Pyr-NH—CH₂-5-[3-am-(H)]-thioph 163.CH₃OOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[5-am-(OH)]-thiaz 164.EtOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[5-am-(OH)]-thiaz 165.nPrOOC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[5-am-(OH)]-thiaz 166.nPrOOC—CH₂—(D)-Cha-Dep-NH—CH₂-2-[5-am-(OH)]-thiaz 167.CH₃OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-3-Me-[2-am-(OH)]-thioph 168.EtOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-3-Me-[2-am-(OH)]-thioph 169.nPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-3-Me-[2-am-(OH)]-thioph 170.CH₃OOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-4-Me-[3-am-(OH)]-thioph 171.EtOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-4-Me-[3-am-(OH)]-thioph 172.nPrOOC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-4-Me-[3-am-(OH)]-thioph 173.cHex-CH₂OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 174.AdaOOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(H)]-thioph 175.cHex-CH₂OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(H)]-thioph 176.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 177.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 178.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(H)]-thioph 179.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(H)]-thioph 180.cHex-CH₂OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 181.AdaOOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(H)]-thioph 182.cHex-CH₂OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(H)]-thioph 183.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 184.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 185.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(H)]-thioph 186.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(H)]-thioph 187.cHex-CH₂OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 188.AdaOOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(H)]-thiaz 189.cHex-CH₂OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(H)]-thiaz 190.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 191.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 192.CH₃—(CH₂)₁₀OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(H)]-thiaz 193.CH₃—(CH₂)₁₅OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(H)]-thiaz 194.cPent-OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 195.cPent-CH₂—OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 196.cHex-OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 197.cPent-OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 198.cPent-CH₂—OOC—CH₂—(D)-Cha-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 199.cHex-OOC—CH₂—(D)-Cha-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 200.cHex-CH₂—OOC—CH₂—(D)-Cha-Pro-NH—CH₂-5-[2-am-(OH)]-thioph 201.cPent-OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 202.cPent-CH₂—OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 203.cHex-OOC—CH₂—(D)-Chg-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 204.cPent-OOC—CH₂—(D)-Cha-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 205.cPent-CH₂—OOC—CH₂—(D)-Cha-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 206.cHex-OOC—CH₂—(D)-Cha-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 207.cHex-CH₂—OOC—CH₂—(D)-Cha-Pro-NH—CH₂-5-[3-am-(OH)]-thioph 208.cPent-OOC—CH₂—(D)-Chg-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 209.cPent-CH₂—OOC—CH₂—(D)-Chg-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 210.cHex-OOC—CH₂—(D)-Chg-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 211.cPent-OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 212.cPent-CH₂—OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 213.cHex-OOC—CH₂—(D)-Cha-Pro-NH—CH₂-2-[4-am-(OH)]-thiaz 214.cHN₄C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 215.cHN₄C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 216.cHN₄C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 217.cHN₄C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 218.cHN₄C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 219.cHN₄C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 220.HONH—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 221.HONH—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 222.HONH—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 223.HONH—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 224.HONH—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 225.cHex-N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 226.cHex-N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 227.cHex-N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 228.cHex-N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 229.cHex-N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 230.cHex-N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 231.iPr-N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 232.iPr-N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 233.iPr-N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 234.iPr-N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 235.iPr-N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 236.iPr-N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 237.CH₃—N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 238.CH₃—N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 239.CH₃—N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 240.CH₃—N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 241.CH₃—N(OH)—OC—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 242.CH₃—N(OH)—OC—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 243.NH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 244.NH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 245.NH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 246.NH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 247.NH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 248.NH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 249.c(CH₂)₅N—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 250.c(CH₂)₅N—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 251.c(CH₂)₅N—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 252.c(CH₂)₅N—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 253.c(CH₂)₅N—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 254.c(CH₂)₅N—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 255.N—Me-4-Pip-O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 256.N—Me-4-Pip-O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 257.N—Me-4-Pip-O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 258.N—Me-4-Pip-O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 259.N—Me-4-Pip-O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 260.N—Me-4-Pip-O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 261.N—Me-4-Pip-O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 262.N—Me-4-Pip-O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 263.N—Me-4-Pip-O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 264.N—Me-4-Pip-O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 265.N—Me-4-Pip-O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 266.N—Me-4-Pip-O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 267.NH₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 268.NH₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 269.NH₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 270.NH₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 271.NH₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 272.NH₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 273.(CH₃)₂N—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 274.(CH₃)₂N—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 275.(CH₃)₂N—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 276.(CH₃)₂N—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 277.(CH₃)₂N—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 278.(CH₃)₂N—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 279.CH₃—NH—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 280.CH₃—NH—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 281.CH₃—NH—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 282.CH₃—NH—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 283.CH₃—NH—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 284.CH₃—NH—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 285.CH₃—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 286.CH₃—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 287.CH₃—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 288.CH₃—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 289.CH₃—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 290.CH₃—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 291.CH₃—O—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 292.CH₃—O—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 293.CH₃—O—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 294.CH₃—O—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 295.CH₃—O—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 296.CH₃—O—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 297.CH₃—NH—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 298.CH₃—NH—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 299.CH₃—NH—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 300.CH₃—NH—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 301.CH₃—NH—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 302.CH₃—NH—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 303.H₂N—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 304.H₂N—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 305.H₂N—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 306.H₂N—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 307.H₂N—SO₂—CH₂—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 308.H₂N—SO₂—CH₂—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 309.(CH₃)₃C—CO₂—CH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 310.(CH₃)₃C—CO₂—CH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 311.(CH₃)₃C—CO₂—CH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 312.(CH₃)₃C—CO₂—CH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 313.(CH₃)₃C—CO₂—CH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 314.(CH₃)₃C—CO₂—CH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 315.(CH₃)₃C—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 316.(CH₃)₃C—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 317.(CH₃)₃C—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 318.(CH₃)₃C—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 319.(CH₃)₃C—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 320.(CH₃)₃C—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 321.cHex-O—CO₂—CH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 322.cHex-O—CO₂—CH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 323.cHex-O—CO₂—CH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 324.cHex-O—CO₂—CH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 325.cHex-O—CO₂—CH₂—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 326.cHex-O—CO₂—CH₂—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 327.cHex-O—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 328.cHex-O—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 329.cHex-O—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 330.cHex-O—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 331.cHex-O—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 332.cHex-O—CO₂—CH(CH₃)—O₂C—CH₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 333.cHex-OCO—C(CH₃)₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 334.cHex-OCO—C(CH₃)₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 335.cHex-OCO—C(CH₃)₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 336.cHex-OCO—C(CH₃)₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 337.cHex-OCO—C(CH₃)₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 338.cHex-OCO—C(CH₃)₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 339.C₂H₅—O—CO—C(CH₃)₂—(D)-Cha-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 340.C₂H₅—O—CO—C(CH₃)₂—(D)-Chg-Pyr-NH—CH₂-2-[4-am-(OH)]-thiaz 341.C₂H₅—O—CO—C(CH₃)₂—(D)-Cha-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 342.C₂H₅—O—CO—C(CH₃)₂—(D)-Chg-Pyr-NH—CH₂-5-[2-am-(OH)]-thioph 343.C₂H₅—O—CO—C(CH₃)₂—(D)-Cha-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph 344.C₂H₅—O—CO—C(CH₃)₂—(D)-Chg-Pyr-NH—CH₂-5-[3-am-(OH)]-thioph

LIST OF ABBREVIATIONS

Adaala: adamantylalanine Adagly: adamantylglycine AIBN:azobisisobutyronitrile Ac: acetyl Ala: alanine am: amidino Asp: asparticacid Aze: azetidinecarboxylic acid Bn: benzyl Boc: tert-butyloxycarbonylBu: butyl c-pent: cyclopentyl Cbz: benzyloxycarbonyl C(CH₂)₅N—:N-piperidinyl Cha: cyclohexylalanine Chea: cycloheptylalanine Cheg:cycloheptylglycine CHN₄C—: tetrazolyl-(3-tetrazolyl- or 5-tetrazolyl)Chg: cyclohexylglycine Cog: cyclooctylglycine Cpa: cyclopentylalanineCpg: cyclopentylglycine TLC: thin layer chromatography DCC:dicyclohexylcarbodiimide Dch: dicyclohexylalanine Dcha:dicyclohexylamine DCM: dichloromethane Dep: 4,5-dehydropipecolic acidDMF: dimethylformamide DIPEA: diisopropylethylamine Dpa: diphenylalanineEt: ethyl Eq: equivalents Gly: glycine fur: furan ham: hydroxyamidinoHOSucc: hydroxysuccinimide HPLC: high performance liquid chromatograpyiPr: isopropyl Me: methyl MPLC: medium pressure liquid chromatographyMTBE: methyl tert-butyl ether NBS: N-bromosuccinimide N—Me-4-Pip-OH:N-methyl-4-piperidinyl alcohol Nog: norbornylglycine Oxaz: oxazole Ph:phenyl Phe: phenylalanine Pic: pipecolic acid PPA: propylphosphonicanhydride Pro: proline Py: pyridine Pyr: 3,4-dehydroproline pyraz:pyrazole pyrr: rrole RT: room temperature RP-18 reversed phase C-18 t:tertiary tBu: tertiary butyl tert: tertiary TBAB: tetrabutylammoniumbromide TEA: triethylamine TFA: trifluoroacetic acid TFAA:trifluoroacetic anhydride thiaz: thiazole thioph: thiophene TOTU:O-[cyano(ethoxycarbonyl)methyleneamino]- N,N,N′,N′-tetramethyluroniumtetrafluoroborate Z: benzyloxycarbonyl ^(n)Pent: n-pentyl neoPent:neopentyl (2,2-dimethyl-1-propyl) nHex: n-hexyl cHex: cyclohexyl nOct:n-octyl O-p-Me-Bn: p-methylbenzyloxy MeO-tetraethoxy: radical fromtetraethylene glycol monomethyl ether

The definitions for the individual substituents in the description andthe claims are as follows:

The term “cycloalkyl” as such or as part of another substituentcomprises saturated, cyclic hydrocarbon groups which contain the statednumber of carbon atoms and in which up to two CH₂ groups may be replacedby oxygen, sulfur or nitrogen atoms. C₃₋₈-Cycloalkyl refers to saturatedalicyclic rings having 3 to 8 C atoms such as, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl,cyclohexylmethyl, cycloheptyl or cyclooctyl, pyrrolidinyl, piperidinyl,morpholinyl. Substituted cyclic hydrocarbons without heteroatoms arepreferred.

The term “alkyl” as such or as part of another substituent means alinear or branched alkyl chain radical of the length stated in eachcase, which may be saturated or unsaturated and in which up to five CH₂groups may be replaced by oxygen, sulfur or nitrogen atoms. In thelatter case, the heteroatoms are separated from one another by at leasttwo carbon atoms. Thus, C₁₋₄-alkyl means, for example, methyl, ethyl,1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl,1-but-2-enyl, 2-butyl, C₁₋₆-alkyl for example C₁₋₄-alkyl, 1-pentyl,2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or3,3-dimethylbutyl. C₁₋₈-Alkyl means in addition to the radicals statedfor C₁₋₄-alkyl for example C₁₋₆-alkyl, heptyl, 2-(2-methoxyethoxy)ethylor octyl.

Preferred are linear or branched saturated alkyl radicals withoutheteroatoms.

The term “alkoxy” as such or as part of another substituent means alinear or branched alkyl chain radical of the length stated in eachcase, which may be saturated or unsaturated and is linked via an oxygenatom to the parent compound in each case. Thus, C₁₋₄-alkoxy means, forexample, methoxy, ethoxy, 1-propoxy, 2-propoxy, 2-methyl-2-propoxy,2-methyl-1-propoxy, 1-butoxy, 2-butoxy.

The term “aryl” as such or as part of another substituent includesmono-, bi- or tricyclic aromatic hydrocarbons such as phenyl, naphthyl,tetralinyl, indenyl, fluorenyl, indanyl, an thracenyl, phenanthrenyl.

The compounds of the formula I may exist as such or in the form of theirsalts with physiologically tolerated acids. Examples of such acids are:hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoricacid, methanesulfonic acid, acetic acid, formic acid, maleic acid,fumaric acid, succinic acid, hydroxysuccinic acid, sulfuric acid,glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronicacid, oxalic acid, ascorbic acid and acetylglycine.

The novel compounds of the formula I can be employed for the followingindications:

-   -   disorders whose pathomechanism is based directly or indirectly        on the proteolytic effect of thrombin,    -   disorders whose pathomechanism is based on the        thrombin-dependent activation of receptors and signal        transductions,    -   disorders associated with stimulation [e.g. by PAI-1, PDGF        (platelet derived growth factor), P-selectin, ICAM-1, tissue        factor] or inhibition (e.g. NO synthesis in smooth muscle cells)        of the expression of genes in body cells,    -   disorders based on the mitogenic effect of thrombin,    -   disorders based on a thrombin-dependent change in the        contractility and permeability of epithelial cells (e.g.        vascular endothelial cells),    -   thrombin-dependent thromboembolic events such as deep vein        thrombosis, pulmonary embolism, myocardial or cerebral infarct,        atrial fibrillation, bypass occlusion,    -   disseminated intravascular coagulation (DIC),    -   reocclusion and for reducing the reperfusion time on        comedication with thrombolytics such as streptokinase,        urokinase, prourokinase, t-PA, APSAC, plasminogen activators        from the salivary glands of animals, and the recombinant and        mutated forms of all these substances,    -   the occurrence of early reocclusion and late restenosis after        PTCA,    -   thrombin-dependent proliferation of smooth muscle cells,    -   accumulation of active thrombin in the CNS (e.g. in Alzheimer's        disease),    -   tumor growth, and to counter the adhesion and metastasis of        tumor cells.

The novel compounds can be employed in particular for the therapy andprophylaxis of thrombin-dependent thromboembolic events such as deepvein thromboses, pulmonary embolisms, myocardial or cerebral infarctsand unstable angina, also for the therapy of disseminated intravascularcoagulation (DIC). They are further suitable for combination therapywith thrombolytics such as streptokinase, urokinase, prourokinase, t-PA,APSAC and other plasminogen activators for reducing the reperfusion timeand increasing the reocclusion time.

Further preferred areas of use are to prevent thrombin-dependent earlyreocclusion and late restenosis after percutaneous transluminal coronaryangioplasty, to prevent thrombin-induced proliferation of smooth musclecells, to prevent the accumulation of active thrombin in the CNS (e.g.in Alzheimer's diseases), to control tumors and to prevent mechanismswhich lead to adhesion and metastasis of tumor cells.

The novel compounds can be administered orally in a conventional way.Administration can also take place with vapors or sprays through thenasopharyngeal space.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. As a rule, the daily dose of activesubstance per person is between about 10 and 2000 mg on oraladministration. This dose can be given in 2 to 4 single doses or once aday as slow-release form.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, for example as uncoated or (film-)coated tablets,capsules, powders, granules, solutions or sprays. These are produced ina conventional way. The active substances can for this purpose beprocessed with conventional pharmaceutical aids such as tablet binders,bulking agents, preservatives, tablet disintegrants, flow regulators,plasticizers, wetting agents, dispersants, emulsifiers, solvents,release-slowing agents, antioxidants and/or propellant gases (cf. H.Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart,1978). The administration forms obtained in this way normally containfrom 0.1 to 99% by weight of the active substance.

EXPERIMENTAL PART

Pharmacological Tests

The rate of absorption of medicines administered orally from thegastrointestinal tract (GIT) is an essential factor in relation to thebioavailability of the medicine. A good rate of absorption is aprecondition for high bioavailability.

Several in vitro models are available for studying intestinalabsorption. Thus, the human colon adenocarcinoma cell lines HT-29,Caco-2 and T84 are routinely employed to investigate various intestinaltransport processes (Madara et al., Am. J. Physiol. 1988, 254:G416–G423; K. L. Audus et al., Pharm. Res. 1990, 7, 435–451). The IEC-18cell line has also shown itself to be a suitable model for investigatingthe permeability of hydrophilic substances through the intestinalmembrane (Ma et al., J. Lab. Clin. Med. 1992 120, 329–41; Duizer et al.,J. Contr. Rel. 1997 49, 39–49).

For the transport experiments (for materials and methods, see R. T.Borchardt, P. L. Smith, G. Wilson, Models for Assessing Drug Absorptionand Metabolism, 1^(st) edition, Plenum Press New York and London, 1996,chapter 2), the cells are cultivated on Transwell polycarbonatemembranes for 17–24 days. The test chamber is arranged so that themembrane divides the apical from the basolateral compartment. Transportof the test substances from the apical side through the cell layer ontothe basolateral side can be measured as a function of the pH gradient,for example apical (pH 6.0)→basolateral (pH 8.0).

After incubation of the cells with the test substance, samples are takenfrom the apical and basolateral sides after a defined time interval(e.g. 24 h). The content of test substance employed and any metabolitesin each of the two compartments is determined by HPLC (comparison ofretention times) and HPLC-MS (elucidation of metabolites) analyses. Thetransport rate is calculated.

It is possible on the basis of the results of these tests to divide testsubstances into the following categories:

+++: very good transport

++: good transport

+: moderate transport

The division of selected samples into said categories has beenundertaken in the following table:

Ex. No. Transport 2 + 10 + 11 +++ 21 ++ 25 ++ 29 ++ 33 +++Pharmacokinetics and Clotting Parameters in Rats

The test substances are dissolved in an isotonic salt solutionimmediately before administration to alert Sprague Dawley rats. Theapplication volumes are 1 ml/kg for the intravenous bolus injection intothe vein of the tail and 10 ml/kg for the oral administration which isconducted via a probang. If not indicated otherwise, blood samples aretaken 1 hour after oral application of 21.5 ml·kg⁻¹ or intravenousapplication of 1.0 mg·kg⁻¹ of the test substance or the respectivevehicle (control). Five minutes before the blood sample is taken, theanimals are narcotized by i.p. application of a 25% urethane solution(dose 1 g·kg⁻¹ i.p.) in a physiological sodium chloride solution. The A.carotis is prepared and catheterized and blood samples (2 ml) in citratevials (1.5 parts citrate plus 8.5 parts blood) are taken. Immediatelyafter the samples are taken the ecarin clotting time (ECT) in the wholebood is determined. After the preparation of the plasma bycentrifugation the plasma-thrombin time and the activated partialthromboplastin time (APTT) are determined by means of a coagulometer.

Clotting Parameters:

Ecarin clotting time (ECT): 100 μl citrate blood are incubated for 2mins at 37° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein,München, BRD). After addition of 100 μl of preheated (37° C.) ecarinreagent (Pentapharm) the time taken for the formation of a fibrin clotis measured.

Activated thromboplastin time (APTT): 50 μl citrate plasma and 50 μl ofthe PTT reagent (Pathrombin, Behring) are mixed and incubated for 2 minsat 37° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein, München,BRD). After addition of 50 μl of preheated (37° C.) calcium chloride thetime taken for the formation of a fibrin clot is measured.

Thrombin time (TT): 100 μl of plasma treated with citrate is incubatedfor 2 mins at 37° C. in a coagulometer (CL 8, Kugel-Typ, Bender &Hobein, München, BRD). After addition of 100 μl of preheated (37° C.)thrombin reagent (Boehringer Mannheim) the time taken for the formationof a fibrin clot is measured.

Pharamacokinetics and Clotting Parameters in Dogs

The test substances are dissolved in an isotonic salt solutionimmediately before administration to alert mongrels. The applicationvolumes are 0.1 ml/kg for the intravenous bolus injection and 1 ml/kgfor the oral application which is conducted via a probang. Before aswell as 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, 360, (ifnecessary after 420, 480 min and 24 hours) after intravenous applicationof 1.0 ml/kg or before as well as 10, 20, 30, 60, 120, 180, 240, 300,360, 480 mins and 24 hours after oral administration of 4.64 ml/kg,respectively, samples of venous blood (2 ml) are taken in citrate vials.Immediately after taking these samples, the ecarin clotting time (ECT)is determined in the whole blood. After separation of the plasma bycentrifugation the plasma thrombin time and the activated partialthromboplastin time (APTT) are determined by means of a coagulometer.

In addition, the anti-F IIa-activity (ATU/ml) and the concentration ofthe substance by its anti-F IIa-activity in plasma is determined bymeans of a chromogenic (S-2238) thrombin assay whereby calibrationcurves with r-hirudin and the test substance were used.

The plasma concentration of the test substance is the basis for thecalculation of the pharmacokinetic parameters: time of the maximumplasma concentration (T max), maximum plasma concentration; plasmahalf-life, t_(0.5); area under the curve (AUC); absorbed part of thetest substance (F).

Clotting Parameters:

Ecarin clotting time (ECT): 100 μl citrate blood are incubated for 2mins at 37° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein,München, BRD). After addition of 100 μl of preheated (37° C.) ecarinreagent (Pentapharm) the time taken for the formation of a fibrin clotis measured.

Activated thromboplastin time (APTT) 50 μl citrate plasma and 50 μl ofthe PTT reagent (Pathrombin, Behring) are mixed and incubated for 2 minsat 37° C. in a coagulometer (CL 8, Kugel-Typ, Bender & Hobein, München,BRD). After addition of 50 μl of preheated (37° C.) calcium chloride thetime taken for the formation of a fibrin clot is measured.

Thrombin time (TT): 100 μl of plasma treated with citrate is incubatedfor 2 mins at 37° C. in a coagulometer (CL 8, Kugel-Typ, Bender &Hobein, München, BRD). After addition of 100 μl of preheated (37° C.)thrombin reagent (Boehringer Mannheim) the time taken for the formationof a fibrin clot is measured.

The compounds of the formula I can be prepared as shown in schemesI–III.

The building blocks A, B, E and D are preferably assembled separatelyand employed in suitably protected form (see schemes I–III) usingprotective groups which are orthogonal in each case and are compatiblewith the synthetic method used (P or P*).

Scheme I describes the linear assembly of molecule I by elimination ofprotective groups from P-D-L (L equal to CONH₂, CSNH₂, CN), coupling ofthe amine H-D-L to the N-protected amino acid P-E-OH to give P-E-D-L,elimination of the N-terminal protective group to give H-E-D-L, couplingto the N-protected amino acid P-B-OH to give P-B-E-D-L, elimination ofthe protective group P to give H-B-E-D-L, subsequent coupling oralkylation with the optionally protected (P)-A-U building block(U=leaving group) or reductive alkylation with (P)-A′-U (U=aldehyde,ketone) or Michael addition with a suitable (P)-A″-C═C derivative togive (P)-A-B-E-D-L. If L is an amide function, this can be converted, atthe protected stages in each case, by dehydration with trifluoroaceticanhydride into the corresponding nitrile function. Amidine syntheses forthienylamidine, furylamidine and thiazolylamidine compounds ofstructural type I starting from the corresponding carboxamides,nitrites, thiocarboxamides and hydroxyamidines are described in a numberof patent applications (see, for example, WO 95/35309, WO 96/178860, WO96/24609, WO 96/25426, WO 98/06741, WO 98/09950). Any protective groupsstill present are then eliminated.

Scheme II describes the linear assembly of molecule I by coupling,alkylation, reductive amination or Michael addition of H-B-P ontoappropriately suitable, optionally protected (P*)-A building blocks[(P*)-A-U (U=leaving group) or (P*)-A′-U (U=aldehyde, ketone) or(P*)-A″-C═C derivative] to give (P*)-A-B-P. Elimination of theC-terminal protective group to give (P*)-A-B-OH is followed by couplingto H-E-P to give (P*)-A-B-E-P, renewed elimination of the C-terminalprotective group to give (P*)-A-B-E-OH and coupling to H-D-L* (L* equalto CONH₂, CSNH₂, CN, C(═NH)NH—R*; R* equal to hydrogen atom orprotective group) to give (P*)-A-B-E-D-L. Reaction of this intermediateto give the final product takes place in analogy to scheme I. Synthesisof the alkoxy- or aryloxyamidines (G=OR) takes place by reacting theappropriate imino thioester salts with O-substituted hydroxylaminederivatives. P is then introduced by transesterification or startingfrom the free acid. To synthesize the oxadiazolones (G and K togetherform a COO group), in particular the 3-substituted1,2,4-oxadiazol-5-ones, the appropriate amide oximes are reacted withcarbonic acid derivatives such as, for example, phosgene, di- andtriphosgene, carbonyldiimidazole or chloroformic esters with addition ofbases (e.g. NaOH, pyridine, tertiary amines) (R. E. Bolton et al.,Tetrahedron Lett. 1995, 36, 4471; K. Rehse, F. Brehme, Arch. Pharm. Med.Chem. 1998, 331, 375).

Scheme III describes a very efficient way for preparing the compounds Iby a convergent synthesis. The appropriately protected building blocks(P*)-A-B-D-B-OH and H-E-D-L or H-E-D-L are coupled together and theresulting intermediates (P*)-A-B-D-B-E-D-L and (P*)-A-B-D-B-E-D-L schemeI are reacted to give the final product.

The N-terminal protective groups employed are Boc, Cbz or Fmoc, andC-terminal protective groups are methyl, tert-butyl and benzyl esters.Amidine protective groups are preferably Boc and Cbz. If theintermediates contain olefinic double bonds, protective groupseliminated by hydrogenolysis are unsuitable.

The required coupling reactions and the conventional reactions forintroducing and eliminating protective groups are carried out under thestandard conditions of peptide chemistry (see M. Bodanszky, A. Bodanszky“The Practice of Peptide Synthesis”, 2^(nd) edition, Springer VerlagHeidelberg, 1994).

Boc protective groups are eliminated using dioxane/HCl, diethylether/HCl, dichloromethane/HCl or TFA/DCM, Cbz protective groups areeliminated by hydrogenolysis or with HF, Fmoc protective groups areeliminated with piperidine. Ester functions are hydrolyzed with LiOH inan alcoholic solvent or in dioxane/water. TFA or dioxane/HCl is used tocleave t-butyl esters.

The reactions were monitored by TLC, normally using the following mobilephases:

A. DCM/MeOH 95:5 B. DCM/MeOH 9:1 C. DCM/MeOH 8:2 D. DCM/MeOH/50% HOAc40:10:5 E. DCM/MeOH/50% HOAc 35:15:5 F. cyclohexane/EA 1:1

Where separations by column chromatography are mentioned, these wereseparations on silica gel using the abovementioned mobile phases.

Reversed phase HPLC separations were carried out with acetonitrile/waterand HOAc buffer.

The starting compounds can be prepared by the following methods:

The building blocks A employed for the alkylation are, for example,tert-butyl α-bromoacetate, adamantyl α-bromoacetate, tert-butylβ-bromopropionate, tert-butyl α-bromopropionate, tert-butylα-bromobutyrate, 2,3-dimethyl-2-butyl α-bromoacetate, THP-protectedbromoethanol, N-tert-butyl-α-bromoacetamide andN,N-diethyl-α-bromoacetamide. The tert-butyl esters mentioned areprepared in analogy to G. Uray, W. Lindner, Tetrahedron 1988, 44,4357–4362, unless they can be purchased. The bromoacetic esters notcommercially available were prepared by reacting bromoacetyl bromidewith the appropriate alcohols, adding pyridine as base.

B building Blocks:

A wide variety of possibilities for the general and specific synthesisof amino acids are available in the literature. A review thereof is tobe found, inter alia, in volume E16d/part 1 of Houben-Weyl, pp. 406 etseq.

Precursors which are frequently employed were diphenylmethyleneglycineethyl ester, diethyl acetamidomalonate and ethyl isocyanoacetate.

Various glycine and alanine derivatives were prepared, for example,starting from ethyl isocyanoacetate and an appropriate ketone oraldehyde (see H.-J. Prätorius, J. Flossdorf, M.-R. Kula Chem. Ber. 1975,108, 3079).

The syntheses of cyclooctylglycine, 2-norbornylglycine,adamantylalanine, g-methylcyclohexylalanine,4-isopropylcyclohex-1-ylalanine, 4-methylcyclohex-1-ylalanine and4-methylcyclohex-1-ylglycine were carried out via the correspondingethyl 2-formylaminoacrylates (U. Schöllkopf and R. Meyer, Liebigs Ann.Chem. 1977, 1174) starting from ethyl isocyanoacetate with the relevantcarbonyl compounds cyclooctanone, 2-norbornanone, 1-formyladamantane,1-formyl-1-methylcyclohexane, 1-formyl-4-isopropylcyclohexane,1-formyl-4-methylcyclohexane and 4-methylcyclohexanone by the followinggeneral methods:

General Method for Synthesizing ethyl 2-formylaminoacrylates

A solution of 100 mmol of ethyl isocyanoacetate in 50 ml of THF wasadded dropwise to 100 mmol of potassium tert-butoxide in 150 ml of THFat 0 to −10° C. After 15 min, 100 mmol of the appropriate carbonylcompound in 50 ml of THF were added at the same temperature, thereaction mixture was allowed slowly to rise to RT, and the solvent wasstripped off in a rotary evaporator. The residue was mixed with 50 ml ofwater, 100 ml of acetic acid and 100 ml of DCM, and the product wasextracted with DCM. The DCM phase was dried over Na₂SO₄, and the solventwas stripped off in a rotary evaporator. The resulting products werealmost pure but could, if necessary, be purified further by columnchromatography on silica gel (mobile phases: ether/petroleum ethermixtures).

General method for amino acid hydrochlorides starting from the ethyl2-formylaminoacrylates

100 mmol of the ethyl 2-formylaminoacrylates were hydrogenated with Pd/C(10%) and hydrogen in 200 ml of glacial acetic acid until the reactionwas complete. The catalyst was then filtered off, the acetic acid wasstripped off as far as possible in a rotary evaporator, and the residuewas refluxed in 200 ml of 50% concentrated hydrochloric acid for 5 h.The hydrochloric acid was stripped off in a rotary evaporator, and theproduct was dried at 50° C. in vacuo and then washed several times withether. The hydrochlorides resulted as pale-colored crystals.

25.0 g of cyclooctylglycine hydrochloride were obtained starting from18.9 g (150 mmol) of cyclooctanone. 26.6 g of 2-norbornylglycinehydrochloride were obtained starting from 16.5 g (150 mmol) of2-norbornanone. 26.0 g of adamantylalanine hydrochloride were obtainedstarting from 19.7 g (120 mmol) of 1-formyladamantane. 16.6 g ofg-methylcyclohexylalanine hydrochloride were obtained starting from 12.6g (100 mmol) of 1-formyl-1-methylcyclohexane. 25.9 g of4-methylcyclohexylglycine hydrochloride were obtained starting from 16.8g (150 mmol) of 4-methylcyclohexanone. 18 g oftrans-4-methylcyclohex-1-ylalanine hydrochloride were-obtained startingfrom 15 g of trans-1-formyl-4-methylcyclohexane. 10 g of3,3-dimethylcyclohex-1-ylalanine hydrochloride were obtained startingfrom 9 g of 3,3-dimethyl-1-formylcyclohexane.

The aldehyde 1-formyl-3,3-dimethylcyclohexane required for the synthesiswas prepared by a method based on that of Moskal and Lensen (Rec. Trav.Chim. Pays-Bas 1987, 106, 137–141):

A solution of n-butyllithium in n-hexane (72 ml, 115 mmol) was addeddropwise over the course of 10 min to a stirred solution of diethylisocyanomethylphosphonate (17 ml, 105 mmol) in 280 ml of anhydrousdiethyl ether at −60° C. The resulting suspension was then stirred at−60° C. for 15 min and, over the course of 10 min, a solution of3,3-dimethylcyclohexanone (13 g, 105 mmol) in 100 ml of anhydrousdiethyl ether was added, keeping the temperature below −45° C. Thereaction mixture was allowed to reach 0° C. and, after stirring at thistemperature for 90 min, 150–200 ml of 38% strength aqueous hydrochloricacid were cautiously added. The mixture was vigorously stirred at roomtemperature for 15 h to complete the hydrolysis. The organic phase wasseparated off and washed with 200 ml each of water, saturated sodiumbicarbonate solution and saturated sodium chloride solution. It wasdried over magnesium sulfate, filtered and concentrated in a rotaryevaporator in order to remove the solvent. The resulting residue wasemployed without further purification as starting material forsynthesizing the amino acid.

Boc-(D)-α-Methylcyclohexylalanine

3.4 g (12.2 mmol) of Boc-(D)-α-methyl-Phe-OH were hydrogenated in 100 mlof MeOH in the presence of 250 mg of 5% Rh on Al₂O₃ under 10 bar ofhydrogen at 50° C. for 24 h. Filtration and stripping off the solventresulted in 2.8 g of Boc-(D)-α-methyl-Cha-OH.

¹H-NMR (DMSO-d₆, δ in ppm): 12 (very broad signal, COOH); 1.7–0.8 (25 H:1.35 (s, Boc), 1.30 (s, Me))

Boc-(3-Ph)-Pro-OH was synthesized in analogy to a method of J. Y. L.Chung et al. (J. Y. L. Chung et al. J. Org. Chem. 1990, 55, 270).

Preparation of Boc-(D,L)Dch-OH

Boc-(D,L)-Dpa-OH (1 mmol) was hydrogenated in 12 ml of MeOH togetherwith catalytic amounts of 5% Rh/Al₂O₃ under 5 bar. Filtration andremoval of the solvent in vacuo resulted in the product in quantitativeyield.

Preparation of cycloheptylglycine, cyclopentylglycine,4-isopropylcyclohexylglycine and 3,3-dimethylcyclohexylglycine

These amino acids were prepared by reacting cycloheptanone,cyclopentanone, 4-isopropylcyclohexanone and 3,3-dimethylcyclohexanone,respectively, with ethyl isocyanoacetate by a method of H.-J. Prätorius(H.-J. Prätorius, J. Flossdorf, M. Kula, Chem. Ber. 1985, 108, 3079)

Preparation of H-D,L-Chea-OH

4.0 g of cycloheptylmethyl methanesulfonate (19.39 mmol), prepared fromcycloheptylmethanol and methanesulfonyl chloride, were refluxed togetherwith 4.9 g of diphenylmethyleneglycine ethyl ester (18.47 mmol), 8.9 gof dry, finely powdered potassium carbonate (64.65 mmol) and 1 g oftetrabutylammonium bromide (3 mmol) in 50 ml of dry acetonitrile underan inert gas atmosphere for 10 h. The potassium carbonate was thenfiltered off, the filtrate was evaporated to dryness, and the crudeproduct was hydrolyzed directly with 20 ml of 2N hydrochloric acid in 40ml of ethanol, stirring at RT for 1.5 h. The reaction solution wasdiluted and then benzophenone was extracted with ethyl acetate in theacidic range, and subsequently H-D,L-Chea-OEt was extracted with DCM inthe alkaline range (pH=9), and the solution was dried over magnesiumsulfate and concentrated in a rotary evaporator. Yield 3.7 g{circumflexover (=)}95% of theory.

Said amino acids were converted with di-tert-butyl dicarbonate inwater/dioxane by conventional methods into the Boc-protected form ineach case and subsequently recrystallized from ethyl acetate/hexanemixtures or purified by column chromatography on silica gel (mobilephases: ethyl acetate/petroleum ether mixtures).

The Boc-protected amino acids were employed as B building blocks asshown in scheme I.

Said amino acids as B building blocks were also in some cases convertedinto the corresponding benzyl esters and linked to the appropriatelyprotected A building blocks. In the case of compounds with an N—Hfunction which was still free, this was subsequently protected with aBoc group, the benzyl ester group was removed by hydrogenation and thebuilding block A-B-OH was purified by crystallization, saltprecipitation or column chromatography. This route is described by wayof example for tBuOOC—CH₂-(Boc) (D)Cha-OH below.

Synthesis of D-cyclohexylalanine benzyl ester

A suspension of 100 g (481 mmol) of D-cyclohexylalanine hydrochloride,104 g (962 mmol) of benzyl alcohol and 109.7 g (577 mmol) ofp-toluenesulfonic acid monohydrate in 2200 ml of toluene was slowlyheated to reflux with a water trap. Evolution of hydrogen chloride anddissolving of the suspension to give a clear solution were observed inthe temperature range 80–90° C. When no further water separated out(about 4 h), 500 ml of toluene were distilled out, the reaction mixturewas allowed to cool overnight, and the resulting residue was filteredoff and washed twice with 1000 ml of hexane each time. The resultingresidue (195 g) was then suspended in 2000 ml of dichloromethane and,after addition of 1000 ml of water, adjusted to pH 9–9.5 by gradualaddition of 50% strength sodium hydroxide solution while stirring. Theorganic phase was separated off, washed twice with 500 ml of water eachtime, dried over sodium sulfate and filtered to remove desiccant, andthe filtrate was concentrated, resulting in 115 g (94%) of the titleproduct as a pale oil.

N-(tert-Butyloxycarbonylmethyl)-D-cyclohexylalanine benzyl ester

115 g (440 mmol) of D-cyclohexylalanine benzyl ester were dissolved in2000 ml of acetonitrile and, at room temperature, 607.5 g (4.40 mol) ofpotassium carbonate and 94.3 g (484 mmol) of tert-butyl bromoacetatewere added, and the mixture was stirred at this temperature for 3 days.Carbonate was filtered off, washing with acetonitrile, the mother liquorwas concentrated (30° C., 20 mbar), the residue was taken up in 1000 mlof methyl tert-butyl ether, and the organic phase was extracted with 5%strength citric acid and saturated sodium bicarbonate solution. Theorganic phase was dried over sodium sulfate, filtered to removedesiccant and concentrated, and the resulting oil (168 g) was employeddirectly in the following reaction.

N-Boc-N-(tert-Butyloxycarbonylmethyl)-D-cyclohexylalanine benzyl ester

The oil (168 g, 447 mmol) obtained in the previous synthesis wasdissolved in 1400 ml of acetonitrile and, after addition of 618 g (4.47mol) of potassium carbonate powder and 107.3 g (492 mmol) ofdi-tert-butyl dicarbonate, stirred at room temperature for 6 days. Thepotassium carbonate was filtered off with suction, washing with about1000 ml of acetonitrile, and the filtrate was concentrated. 230 g of therequired product were obtained.

N-Boc-N-(tert-Butyloxycarbonylmethyl)-D-cyclohexylalaninecyclohexylammonium salt

115 g of N-Boc-N-(tert-butyloxycarbonylmethyl)-D-cyclohexylalaninebenzyl ester were dissolved in 1000 ml of pure ethanol and hydrogenatedin the presence of 9 g of 10% Pd on active carbon with hydrogen underatmospheric pressure at 25–30° C. for 2 h. Filtration and removal of thesolvent in a rotary evaporator resulted in 100 g (260 mmol) of a yellowoil which was taken up in 1600 ml of acetone and heated to reflux. Theheating bath was removed, and a solution of 27 g (273 mmol) ofcyclohexylamine in acetone was quickly added through a dropping funnel.The required salt crystallized out on cooling the reaction mixture toroom temperature. The solid was filtered off, washed with 200 ml ofacetone and, for final purification, recrystallized once more fromacetone. Drying of the residue in a vacuum oven at 30° C. resulted in70.2 g of the required salt as a white powder.

N-Boc-N-(tert-Butyloxycarbonylmethyl)-D-cyclohexylglycinecyclohexylammonium salt was prepared in an analogous way fromcyclohexylglycine as precursor.

N-Boc-N-(tert-Butyloxycarbonylethyl)-D-cyclohexylalaninecyclohexylammonium salt a) tert-Butyl 3-bromopropionate

-   -   16.64 g (109 mmol) of bromopropionic acid, 150 ml of condensed        2-methylpropene and 2 ml of concentrated sulfuric acid were        placed at −30° C. under a countercurrent of nitrogen in a glass        vessel suitable for an autoclave, tightly closed and stirred at        room temperture for 72 h. For workup, the reaction vessel was        again cooled to −30° C., and the reaction solution was        cautiously poured into 200 ml of ice-cold saturated sodium        bicarbonate solution. Excess 2-methylpropene was allowed to        evaporate off with stirring, the residue was extracted three        times with 50 ml of dichloromethane each time, the combined        organic phases were dried over sodium sulfate, the desiccant was        filtered off, and the solution was concentrated under waterpump        vacuum. The oily residue was purified by column chromatography        (mobile phase n-hexane, later n-hexane/diethyl ether 9:1). 18.86        g of the title compound were obtained.)

b) N-(tert-Butyloxycarbonylethyl)-D-cyclohexylalanine benzyl ester

-   -   49.4 g (189 mmol) of D-cyclohexylalanine benzyl ester were        dissolved in 250 ml of acetonitrile and, after addition of 31.6        g (151 mmol) of tert-butyl bromopropionate at room temperature,        refluxed for 5 days. The resulting precipitate was filtered off        and washed several times with acetonitrile, the filtrate was        concentrated under waterpump vacuum, the residue was taken up in        350 ml of dichloromethane, and the organic phase was extracted        with 5% strength citric acid and saturated sodium bicarbonate        solution. The organic phase was dried over sodium sulfate,        filtered to remove desiccant and concentrated. The oily residue        was purified by column chromatography (mobile phase        dichloromethane, later dichloromethane/methanol 95:5). A        slightly impure oil was obtained and was employed directly in        the next reaction.)

c) N-Boc-N-(tert-Butyloxycarbonylethyl)-D-cyclohexylalanine benzyl ester

-   -   The oil obtained in the previous synthesis (30 g, max. 70 mmol)        was dissolved in 150 ml of acetonitrile and, after addition of        28 ml (160 mmol) of diisopropylethylamine and 19.2 g (88 mmol)        of di-tert-butyl dicarbonate, stirred at room temperature for 3        days. The reaction mixture was concentrated in a rotary        evaporator under waterpump vacuum, the residue was taken up in        n-hexane and washed five times with 3 ml of a 5% strength citric        acid solution each time, the combined organic phases were dried        over sodium sulfate, the desiccant was filtered off, and the        residue after concentration was subjected to separation by        column chromatography (mobile phase hexane/ethyl acetate 95:5).        32.66 g (64 mmol) of the required product were obtained.

d) N-Boc-N-(tert-Butyloxycarbonylethyl)-D-cyclohexylalaninecyclohexylammonium salt

-   -   32.66 g (64 mmol) of        N-Boc-N-(tert-butyloxycarbonylethyl)-D-cyclohexylalanine benzyl        ester were dissovled in 325 ml of pure ethanol and hydrogenated        with hydrogen under atmospheric pressure at 25–30° C. in the        presence of 3 g of 10% Pd on active carbon for 14 h. Filtration        of the solution through Celite®, washing with ethanol and        removal of the solvent in a rotary evaporator resulted in 26.7 g        of a yellow oil, which was taken up in acetone and heated to        reflux. The heating bath was removed, and a solution of 7 g (70        mmol) of cyclohexylamine in acetone was quickly added through a        dropping funnel. The required salt crystallized out on cooling        the reaction mixture to room temperature. The solid was filtered        off, washed with 25 ml of acetone and, for final purification,        recrystallized once more from acetone. Drying of the residue in        a vacuum oven at 30° C. resulted in 26.6 g (54 mmol) of the        required salt as a white powder.

N-Boc-N-(tert-Butyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline

-   a) N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 ml), and    HCl in dioxane (4N, 30 ml) was added. After refluxing for 12 h, the    solvent was removed in a rotary evaporator and H-Pyr-OMe    hydrochloride was obtained as product. Yield: 3.84 g (100%).-   b) N-(t-BuO₂C—CH₂)—N-Boc-(D)-Cha-OH (8 g, 20.75 mmol) was dissolved    in dichloromethane (75 ml) and, at −10° C., ethyldiisopropylamine    (15.5 ml, 89.24 mmol) was added. After stirring at this temperature    for 5 min, a solution of H-Pyr-OMe hydrochloride (3.4 g, 20.75 mmol)    in dichloromethane (25 ml) was added dropwise. A solution of    propanephosphonic anhydride in ethyl acetate (50% strength, 20 ml,    26.96 mmol) was then added dropwise, and the mixture was stirred at    −10 to 0° C. for 2 h. The mixture was diluted with dichloromethane    and washed with saturated sodium bicarbonate solution (2×80 ml), 5%    strength citric acid solution (2×15 ml) and saturated sodium    chloride solution (1×20 ml). The organic phase was dried over sodium    sulfate, and the solvent was removed in a rotary evaporator. The    crude product was purified by flash chromatography (silica gel,    dichloromethane/methanol=95/5). Yield: 6.2 g (60%).-   c) N-(t-BuO₂C—CH₂)—N-Boc-(D)-Cha-Pyr-OMe (5.5 g, 11.12 mmol) was    dissolved in dioxane (40 ml) and, after addition of sodium hydroxide    solution (1N, 22.2 ml, 22.24 mmol), stirred at room temperature for    2 h. The dioxane was removed in a rotary evaporator, and the aqueous    phase was washed with ethyl acetate and acidified to pH 1–2 with    potassium bisulfate solution (20% strength). The aqueous phase was    extrcted with dichloromethane, and the combined organic phases were    dried over sodium sulfate. Yield: 5 g (94%), colorless foam.    Recrystallization from n-hexane saturated with water afforded    colorless crystals (m.p.=158–160° C.).

N-Boc-N-(tert-Butyloxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline

This compound was prepared in an analogous manner fromN-Boc-N-(tert-butyloxycarbonylmethyl)-(D)-cyclohexylglycine and3,4-dehydroproline methyl ester.

(L)3,4-Dehydroproline employed as E building block can be purchased, and(D,L)-4,5-dehydropipecolic acid can be prepared by the method of A.Burgstahler, C. E. Aiman J. Org. Chem. 25 (1960), 489 or C. Herdeis, W.Engel Arch. Pharm 326 (1993), 297 and subsequently converted with(Boc)₂O into Boc-(D,L)-Dep-OH.

The D building blocks were synthesized as follows:

5-Aminomethyl-2-cyanothiophene

This building block was prepared as described in WO 95/23609

4-Aminomethyl-2-cyanothiophene a) 2-Bromo-4-formylthiophene

-   -   36 g (320 mmol) of 3-formylthiophene were dissolved in 600 ml of        methylene chloride and cooled to 5° C., 100 g (750 mmol) of        aluminum trichloride were added in portions, and the reaction        mixture was then refluxed. A solution of 59 g (19 ml, 360 mmol)        of bromine in 40 ml of methylene chloride was added dropwise        over the course of 45 min, and the reaction was allowed to        continue under reflux for 4 h. After cooling, the reaction        solution was poured into 600 g of ice-water and extracted with        methylene chloride, and the organic phase was washed with        saturated sodium bicarbonate solution, dried over magnesium        sulfate and concentrated in a rotary evaporator. 64.5 g of crude        product were obtained and were purified by column chromatography        (silica gel, methylene chloride/petroleum ether) to result in a        total of 56.5 g of slightly impure product.

b) 2-Cyano-4-formylthiophene

-   -   7.6 g (85 mmol) of copper(I) cyanide were added to a solution of        13.53 g (70.82 mmol) of 2-bromo-4-formylthiophene in 25 ml of        DMF, and the reaction mixture was refluxed for 3.5 h, during        which the originally pale green suspension changed into a black        solution. After addition of water, the reaction mixture was        extrated several times with ethyl acetate, and the organic        phases were combined, washed with saturated brine, dried over        sodium sulfate and concentrated in a rotary evaporator under        gentle vacuum. Addition of ether to the residue (7 g) resulted        in 1.6 g of pure product. The mother liquor was purified        together with the crude products from other batches by        chromatography (silica gel, methylene chloride/petroleum ether        1:1). A total of 56.5 g of 2-bromo-4-formylthiophene was reacted        to give 12.6 g of pure 2-cyano-4-formylthiophene (31% yield).

c) 2-Cyano-3-hydroxymethylthiophene

-   -   3.47 g (91.8 mmol) of sodium borohydride were added in portions        to a suspension of 12.6 g (91.8 mmol) of        2-cyano-4-formylthiophene in 200 ml of ethanol, and the reaction        mixture was stirred at room temperature for 2 h, during which it        slowly formed a clear solution. The residue after concentration        in vacuo was taken up in ethyl acetate and washed successively        with saturated brine, 5% strength citric acid and saturated        brine, and the organic phase was dried with sodium sulfate and        concentrated in vacuo to result in 11.7 g of almost pure product        (yield 91.5%).

d) 3-Bromomethyl-2-cyanothiophene

-   -   11.7 g (84.07 mmol) of 2-cyano-3-hydroxymethylthiophene were        dissolved together with 24.1 g (91.87 mmol) of        triphenylphosphine in 100 ml of THF at room temperature and,        while cooling (ice bath), 30.47 g (91.87 mmol) of        tetrabromomethane were added in portions. Stirring at room        temperature for 3 hours was followed by concentration in vacuo        and purification by chromatography over silica gel (methylene        chloride/petroleum ether) to result in 18.8 g of pale yellow        crystalline product still containing petroleum ether.

e) 4-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-2-cyanothiophene

-   -   18.81 g of 3-bromomethyl-2-cyanothiophene (crude product,        maximum 84.07 mmol) were dissolved in 160 ml of THF and cooled        to 5° C., and 3.07 g (102.4 mmol) of 80% sodium hydride        suspension were added in portions. Subsequently, 22.25 g (102.4        mmol) of di-tert-butyl iminodicarboxylate dissolved in 160 ml of        THF were added dropwise at 5° C., and the mixture was then        stirred at room temperature overnight. Since conversion was        incomplete according to TLC, the mixture was heated at 30–35° C.        for 4.5 h. After cooling to 0–5° C., 33 ml of saturated ammonium        chloride solution were slowly added dropwise, THF was distilled        off in vacuo, the residue was extracted several times with ethyl        acetate, and the ethyl acetate phases were washed with saturated        brine, dried over sodium sulfate and concentrated in a rotary        evaporator. The viscous red residue (34.61 g) was employed as        crude product in the next reaction.

f) 4-Aminomethyl-2-cyanothiophene hydrochloride

-   -   34.61 g of        4-[N,N-bis(tert-butoxycarbonyl)aminomethyl]-2-cyanothiophene        (crude product, maximum 84.07 mmol) were dissolved in 600 ml of        ethyl acetate, cooled to 0–5° C., saturated with HCl gas and        warmed to room temperature. After 3 h, the resulting suspension        was concentrated in a rotary evaporator and codistilled several        times with methylene chloride, and the residue was extracted by        stirring with ether and dried in vacuo. 13.85 g of product were        obtained as a pale powder. Yield over two stages 94.3%.

2-Aminomethyl-4-cyanothiophene a) 4-Cyanothiophene-2-carbaldehyde

-   -   49.3 g (258.05 mmol) of 4-bromothiophene-2-carbaldehyde and 27.8        g (310.41 mmol) of copper(I) cyanide were suspended in 130 ml of        absolute DMF and refluxed for 8 h. The solvent was removed in a        rotary evaporator at 40° C., and the residue was suspended in        ethyl acetate and transferred into a Soxhlet apparatus. The        residue was extracted overnight, the yellow solution was dried        over sodium sulfate and concentrated in a rotary evaporator, and        the resulting yellow solid was recrystallized from ether to        result in 25.3 g of product (80% of theory).

b) 4-Cyanothiophene-2-carbaldehyde oxime

-   -   11.6 g (84.6 mmol) of 4-cyanothiophene-2-carbaldehyde were        dissolved in 140 ml of methanol, and 12.3 g (116.1 mmol) of        sodium carbonate were added. Then 6.5 g (93.5 mmol) of        hydroxylamine hydrochloride were added in portions while cooling        at 15° C., and the mixture was stirred at 10° C. for 2 h. After        addition of 80 ml of water, the reaction mixture was extracted        five times with 50 ml of diethyl ether each time, the organic        phase was dried over sodium sulfate, and the solvent was removed        in vacuo to result in 12.5 g of the required product as a yellow        crystalline powder (96% of theory).

c) 2-Aminomethyl-4-cyanothiophene hydrochloride

-   -   11.22 g (171.64 mmol) of fine zinc dust were added cautiously in        several small portions to a solution of 4.65 g (30.60 mmol) of        4-cyanothiophene-2-carbaldehyde oxime in 50 ml of        trifluoroacetic acid cooled to 0–5° C. in such a way that the        temperature did not exceed 15° C. After stirring at room        temperature for 3 h and decantation from excess zinc, the        trifluoroacetic acid was substantially removed in vacuo (oil        pump), the remaining oil was cooled to 0° C., and a mixture of        150 ml of 3N sodium hydroxide solution and 2 l of methylene        chloride which had been cooled to 0° C. was added in portions.        Insolubles were removed by filtration and then the organic phase        was separated off, the aqueous phase was extracted eight times        with 20 ml of methylene chloride, the collected organic phases        were dried over sodium sulfate and then, while cooling in ice,        20 ml of 6M methanolic hydrochloric acid were added. The product        precipitated in the form of the hydrochloride as a white solid,        crystallization was completed by cooling the suspension at 4° C.        overnight. 2.2 g of product were obtained as colorless needles        (50% of theory).

5-Aminomethyl-3,4-dimethylthiophene-2-carboxamide hydrochloride

19 g (105.42 mmol) of 5-cyano-3,4-dimethylthiophene-2-carboxamide weresuspended in 760 ml of methanol and 110 ml of 2N hydrochloric acidsolution and, after addition of 9.5 g of Pd on carbon (10%),hydrogenated at room temperature. After uptake of 4.7 l of hydrogen (4h), methanol was distilled out in vacuo, and the aqueous phase wasextracted three times with ethyl acetate and then freeze dried. 16.3 gof the required product were obtained as a white solid (70.4% oftheory).

5-Aminomethylisoxazole-3-carboxamide a) Ethyl5-chloromethylisoxazole-3-carboxylate

-   -   21.2 g (210 mmol) of triethylamine were added dropwise to a        stirred mixture of 30 g (198 mmol) of ethyl        2-chloro-2-hydroxyiminoacetate and 150 ml of propargyl chloride        cooled to 10–15° C. and, after stirring at room temperature for        1 h, water was added, the mixture was extracted with ether, and        the organic phase was dried over magnesium sulfate and        concentrated in a rotary evaporator. The residue was distilled        under 0.5 Torr, the product distilling over at 116–122° C.

b) 5-Chloromethylisoxazole-3-carboxylic acid

-   -   47.3 g (250 mmol) of 5-chloromethylisoxazole-3-carboxylate in        150 ml of ethanol were mixed with 14 g (250 mmol) of potassium        hydroxide, and the reaction mixture was stirred at 60–70° C. for        6 h. After cooling and concentration in vacuo, the residue was        taken up in water and extracted with ether, the aqueous phase        was acidified with hydrochloric acid and then extracted several        times with ether, and the ether phase was dried over sodium        sulfate and concentrated in vacuo (oil pump, 50° C.). 31 g of        the required product were obtained (77% of theory).

c) 5-Chloromethylisoxazole-3-carbonyl chloride

-   -   120 g (743 mmol) of 5-chloromethylisoxazole-3-carboxylic acid        were refluxed together with 500 ml of thionyl chloride and 2        drops of pyridine for 10 h, then concentrated in vacuo and        subsequently distilled under 20 Torr. The product distilled at        125–133° C. 78 g (58% of theory) were obtained.

d) 5-Chloromethylisoxazole-3-carboxamide

-   -   Ammonia was passed into a solution of 10 g (55.56 mmol) of        5-chloromethylisoxazole-3-carbonyl chloride in 100 ml of        methylene chloride at 10–15° C. for 1 h, and the mixture was        then stirred at room temperature for 1 h. After the solution had        been cooled to 0° C., the precipitate was filtered off with        suction and wahsed with a little cold methylene chloride, and        the residue was extracted by stirring with water twice to remove        ammonium salts. Drying in vacuo resulted in 6.58 g of pure        product as a pale powder (74% of theory).

e) 5-Aminomethylisoxazole-3-carboxamide hydrochloride

-   -   2.44 g (15.2 mmol) of 5-chloromethylisoxazole-3-carboxamide were        added to a mixture of 100 ml of concentrated ammonia solution        and 72 ml of methanol, the reaction solution was warmed to        40° C. and, during this, continuously saturated with ammonia        gas. The precursor had reacted after 6 h. The methanol was        removed in vacuo, the aqueous phase was extracted twice with        methylene chloride, and then the aqueous phase was carefully        evaporated to dryness in vacuo. The solid white residue was        employed as crude product in the couplings.

2-Aminomethyloxazole-4-thiocarboxamide and2-aminomethylthiazole-4-thiocarboxamide were prepared as described by G.Videnov, D. Kaier, C. Kempter and G. Jung Angew. Chemie (1996) 108,1604, deprotecting the N-Boc-protected compounds described therein withethereal hydrochloric acid in ethylene chloride.

4-Aminomethylthiazole-2-thiocarboxamide a) Monothiooxamide

-   -   Monothiooxamide was prepared starting from ethyl thiooxamate by        the method of W. Walter, K.-D. Bode Liebigs Ann. Chem. 660        (1962), 74–84.

b) 2-Carbamoyl-4-chloromethylthiazole

-   -   10 g (96 mmol) of ethyl thiooxamate were introduced into 170 ml        of n-butanol and, after addition of 26 g (204 mmol) of        1,3-dichloroacetone, heated at 112° C. under nitrogen for 90        min. The reaction mixture was then concentrated in vacuo, and        the residue was extracted by stirring with n-hexane (120 ml).        This resulted in 10 g of pure product.

c) 4-Boc-Aminomethyl-2-carbamoylthiazole

-   -   10 g (56.6 mmol) of 2-carbamoyl-4-chloromethylthiazole were        introduced into an ammonia-saturated solution of 350 ml of        methanol and 80 ml of 25% strength aqueous ammonia solution. The        reaction mixture was heated at 40–42° C., while continuing to        saturate with ammonia, for 6 h, and was then concentrated in        vacuo and codistilled with methanol, and the residue was then        extracted by stirring firstly with ether and then with acetone.        7.6 g of crude product which still contained a little ammonium        chloride were thus isolated. To remove this byproduct, the crude        product was reacted with (Boc)₂O in aqueous dioxane solution and        the protected compound was purified by column chromatography.        This resulted in 4.95 g of pure product.)

d) 4-Boc-Aminomethyl-2-cyanothiazole

-   -   4.95 g (19.24 mmol) of 4-Boc-aminomethyl-2-carbamoylthiazole        were introduced into 90 ml of methylene chloride and 16.7 ml        (97.44 mmol) of diisopropylethylamine and, after cooling to 0°        C., a solution of 6.35 ml of trifluoroacetic anhydride in 10 ml        of methylene chloride was added dropwise at 0 to 5° C., and the        mixture was then warmed to room temperature (TLC check). Then 25        ml of water were added and, after stirring at room temperature        for 30 min and adjustment to pH 2.5 with 10% strength citric        acid solution, the organic phase was washed several times, dried        with magnesium sulfate and concentrated in vacuo. 5.4 g of pale        brownish viscous crude product were obtained and were employed        without further purification in the next stage.)

e) 4-Boc-Aminomethyl-2-thiocarbamoylthiazole

-   -   The crude product (max 19.24 mmol) obtained from d) was        dissolved in 65 ml of pyridine and 5 ml of triethylamine,        saturated with hydrogen sulfide and left to stand at room        temperature over the weekend. The reaction mixture was then        concentrated in vacuo, taken up in a mixture of ether and ethyl        acetate, washed with 10% strength citric acid solution and        water, dried over magnesium sulfate and concentrated in vacuo.        This resulted in 6.0 g as a pale yellow solid foam.

f) 4-Aminomethyl-2-thiocarbamoylthiazole hydrochloride

-   -   The product obtained from the preceding experiment was taken up        in 100 ml of methylene chloride and, after addition of 30 ml of        approx. 5 molar ethereal hydrochloric acid solution, stirred at        room temperature overnight. The reaction mixture was then        evaporated to dryness in vacuo, codistilled with ether several        times and then extracted by stirring with methylene chloride.        4.15 g of the required product were obtained as a pale yellow        amorphous substance.

4-Amidino-2-(N-Boc-aminomethyl)-5-methylthiazole×HOAc a) α-Acetylglycinemethyl ester hydrochloride

-   -   Potassium tertiary butoxide (17.8 g, 157.9 mmol) was introduced        into THF (120 ml) and, at −70° C., a solution of        N-(diphenylmethylidene)glycine methyl ester (40 g, 157.9 mmol)        in THF (60 ml) was added. After stirring at this temperature for        30 min, the yellowish solution was added dropwise to a solution        of acetyl chloride (12.4 g, 157.9 mmol) in THF (70 ml) at        −70° C. After stirring at this temperature for 1.75 h, 3N HCl        (160 ml) was added and the yellowish suspension was then stirred        at room temperature for 10 min. The THF was removed in a rotary        evaporator at room temperature, and the remaining aqueous phase        was washed 3× with diethyl ether. The aqueous phase was freeze        dried and the residue was extracted by stirring with methanol.        The methanolic solution of the product was evaporated in a        rotary evaporator at 35° C. Yield: 26.4 g (157.9 mmol, quant.,        yellowish solid).

b) Boc-Gly-(α-Acetyl-Gly)-OMe

-   -   Boc-Gly-OH (24.05 g, 137.27 mmol) was introduced into THF        (400 ml) and triethylamine (13.87 g, 137.19 mmol) was added. The        colorless solution was cooled to −20° C. and, at this        temperature, a solution of isobutyl chloroformate (18.75 g,        137.28 mmol) in THF (20 ml) was added dropwise. The colorless        suspension was stirred at −20° C. for 30 min and then        α-acetylglycine methyl ester hydrochloride (23.0 g, 137.3 mmol)        was added in portions. After stirring at −20° C. for 30 min, a        solution of triethylamine (13.87 g, 137.19 mmol) in THF (20 ml)        was added dropwise over the course of 45 min. Stirring at        −20° C. for 4 h was followed by stirring at RT for 12 h. The        residue was filtered off with suction and washed with THF, and        the combined THF phases were concentrated in a rotary        evaporator. Yield: 44.1 g (pale brownish oil).

¹H-NMR (270 MHz, CDCl₃) δ=1.45 (s, 9H), 2.40 (s, 3H), 3.85 (s, 3H), 3.90(d, J=6.5 Hz, 2H), 5.25 (d, J=6.5 Hz, 1H), 7.30 (sbr, 1H).

c) Methyl 2-(N-Boc-aminomethyl)-5-methylthiazole-4-carboxylate

-   -   Boc-Gly-(α-Acetyl-Gly)-OMe (39.8 g, 138.2 mmol) was introduced        into THF (400 ml) and, at room temperature, Lawesson's reagent        (96.6 g, 238.8 mmol) was added in portions. The yellowish        solution was then refluxed for 1.5 h. The THF was removed in a        rotary evaporator. The residue (reddish brown oil) was extracted        by stirring with diethyl ether (600 ml). The ether phase was        decanted off the undissolved brownish oil and washed        successively with 5% strength citric acid (2×), saturated NaHCO₃        solution (9×) and water (2×). After drying (MgSO₄), the solvent        was removed in a rotary evaporator. Yield: 22.0 g (77 mmol, 56%,        pale brownish solid).

¹H-NMR (270 MHz, CDCl₃) δ=1.50 (s, 9H), 2.75 (s, 3H), 3.95 (s, 3H), 4.55(d, J=6.5 Hz, 2H), 5.45 (t, J=6.5 Hz, 1H). (Main rotamer in relation toBoc group)

d) 2-(N-Boc-Aminomethyl)-5-methylthiazole-4-carboxylic acid

-   -   Methyl 2-(N-Boc-aminomethyl)-5-methylthiazole-4-carboxylate        (22.0 μg, 77 mmol) was dissolved in ethanol (100 ml), and a        solution of LiOH (2.2 g, 92 mmol) in water (50 ml) was added.        After stirring at room temperature for 30 min, the ethanol was        removed in a rotary evaporator, and the remaining solution was        diluted with water (70 ml). The aqueous phase was washed with        ethyl acetate (3×) and adjusted to pH 2 with 20% strength NaHSO₄        solution, whereupon a pale brownish oil separated out. The        aqueous phase was extracted with dichloromethane, and the        combined organic extracts were dried (MgSO₄) and concentrated in        vacuo. The pale brownish residue was extracted by stirring in        diisopropyl ether. The remaining colorless precipitate was        filtered off with suction and washed with diisopropyl ether.        Yield: 6.9 g (25.4 mmol, 33%, colorless solid).

¹H-NMR (270 MHz, DMSO-d₆) δ=1.40 (s, 9H), 2.65 (s, 3H), 4.30 (d, J=6.5Hz, 2H), 7.80 (t, J=6.5 Hz, 1H).

e) 2-(N-Boc-Aminomethyl)-5-methylthiazole-4-carboxamide

-   -   2-(N-Boc-Aminomethyl)-5-methylthiazole-4-carboxylic acid (6.8 g,        25 mmol) was dissolved in THF (100 ml), and triethylamine (2.53        g, 25 mmol) was added. After cooling to −20° C., a solution of        isobutyl chloroformate (3.41 g, 25 mmol) in THF (10 ml) was        added dropwise. After stirring at −20° C. for 30 min, gaseous        ammonia was passed into the pale brownish suspension for 45 min.        It was then warmed to room temperature. The residue was filtered        off with suction and extracted with THF, and the filtrates were        concentrated.

Yield: 6.9 g (25 mmol, quant.).

¹H-NMR (270 MHz, DMSO-d₆) δ=1.40 (s, 9H), 2.65 (s, 3H), 4.30 (m, 2H),7.40 (sbr, 1H), 7.50 (sbr, 1H), 7.80 (t, J=6.5 Hz, 1H).

f) 4-Cyano-2-(N-Boc-aminomethyl)-5-methylthiazole

-   -   2-(N-Boc-Aminomethyl)-5-methylthiazole-4-carboxamide (6.8 g, 25        mmol) was introduced into dichloromethane (120 ml). After        cooling to 0° C., diisopropylethylamine (15.84 g, 122.8 mmol)        was added dropwise. Then, at −5° C., a solution of        trifluoroacetic anhydride (8.25 g, 39.3 mmol) in dichloromethane        (20 ml) was added dropwise over the course of min. After        stirring at 0° C. for 30 min, the reaction mixture was warmed to        room temperature and then stirred for 12 h. It was diluted with        dichloromethane (100 ml) and washed with 20% strength citric        acid, saturated NaHCO₃ solution and saturated NaCl solution. The        organic phase was dried (MgSO₄) and concentrated in vacuo.        Yield: 6.3 g (25 mmol, quant.).

g) 4-Amidino-2-(N-Boc-aminomethyl)-5-methylthiazole×CH₃COOH

-   -   4-Cyano-2-(N-Boc-aminomethyl)-5-methylthiazole (5.5 g, 21.74        mmol) was dissolved in methanol (15 ml) and N-acetylcysteine        (4.1 g, 25.12 mmol) was added. The mixture was then heated to        60° C., and ammonia was passed in for 22 h. The mixture was        diluted with methanol and passed over an acetate ion exchanger.        The methanol was removed in a rotary evaporator, and the residue        was extracted by stirring with acetone. The colorless residue        was filtered off with suction and dried in vacuo. Yield: 4.75 g        (14.4 mmol, 66%, colorless solid).

¹H-NMR (400 MHz, DMSO-d₆) δ=1.40 (s, 9H), 1.80 (s, 3H), 2.60 (s, 3H),4.35 (d, J=6.5 Hz, 2H), 7.90 (t, J=6.5 Hz, 1H).

2-Aminomethyl-5-amidino-4-methylthiazole×2 HCl a) N-Boc-Glycinethioamide

-   -   N-Boc-Glycinonitrile (12.0 g, 76.8 mmol) and diethylamine (0.16        ml, 2.1 mmol) were dissolved in toluene (100 ml). The solution        was cooled to −10° C., saturated with hydrogen sulfide and then        stirred at room temperature overnight. The precipitate which        formed was filtered off with suction and washed with toluene.        The product was dried in vacuo at 45° C.

Yield: 13.2 g (69.4 mmol, 90.3%, yellowish solid).

¹H-NMR (270 MHz, DMSO-d₆) δ=1.40 (s, 9H), 3.80 (d, J=7 Hz, 2H), 7.05 (t,J=7 Hz, 1H), 9.0 (sbr, 1H), 9.65 (sbr, 1H).

b) Methyl 2-(N-Boc-aminomethyl)-4-methylthiazole-5-carboxylate

-   -   N-Boc-Glycinethioamide (10.0 g, 52.6 mmol) was introduced into        methanol (70 ml) and methyl 2-chloracetate (7.9 g, 52.6 mmol)        was added. The mixture was heated at 60° C. for 2 h and then        stirred at room temperature for 48 h. The methanol was removed        in a rotary evaporator, and the residue was extracted by        stirring with acetone/diethyl ether. The remaining precipitate        was filtered off with suction and the filtrate was concentrated.        The solid obtained from the filtrate was the product (pure        according to TLC and HPLC).

Yield: 8.7 g (30.4 mmol, 57.8%).

ESI-MS: 287 (M+H⁺).

c) 2-(N-Boc-Aminomethyl)-4-methylthiazole-5-carboxylic acid

-   -   Methyl 2-(N-Boc-aminomethyl)-4-methylthiazole-5-carboxylate (2.8        g, 9.74 mmol) was dissolved in 1,4-dioxane (30 ml), and 1N        sodium hydroxide solution (19 ml) was added. After stirring at        room temperature for 4 h, the 1,4-dioxane was removed in a        rotary evaporator. The residue was diluted with water and washed        with ethyl acetate. The aqueous phase was acidified with 20%        strength potassium bisulfate solution, and the resulting        precipitate was filtered off with suction and washed with water.        The product obtained in this way was dried in a vacuum oven at        40° C. Yield: 2.5 g.

d) 2-(N-Boc-Aminomethyl)-4-methylthiazole-5-carboxamide

-   -   2-(N-Boc-Aminomethyl)-4-methylthiazole-5-carboxylic acid (12.6        g, 46.27 mmol) was dissolved in dichloromethane (460 ml) and        dimethylformamide (0.4 ml). After cooling to 0° C., a solution        of oxalyl chloride (6.46 g, 50.90 mmol) in dichloromethane        (40 ml) was added dropwise over the course of 30 min. After        stirring at 0° C. for 2 h, the mixture was cooled to −20° C.        and, at this temperature, ammonia was passed in until the        reaction was complete. It was then warmed to room temperature        and washed with water. The resulting precipitate was filtered        off with suction. The organic phase was washed with 5% strength        citric acid solution, dried (MgSO₄) and concentrated in a rotary        evaporator. The resulting solid was combined with the previously        filtered precipitate and dried in a vacuum oven at 50° C. Yield:        9.8 g (36.12 mmol, 78%).

e) 2-(N-Boc-Aminomethyl)-5-cyano-4-methylthiazole

-   -   2-(N-Boc-Aminomethyl)-4-methylthiazole-5-carboxamide (11.13 g,        41.02 mmol) was suspended in dichloromethane (75 ml) and cooled        to 0° C. At this temperature, firstly ethyldiisopropylamine        (17.86 ml, 102.55 mmol) and then slowly a solution of        trifluoroacetic anhydride (6.56 ml, 47.17 mmol) in        dichloromethane (20 ml) were added. After stirring for 1 h, the        mixture was diluted with dichloromethane and washed with 5%        strength citric acid solution. After drying (MgSO₄) and removal        of the solvent in a rotary evaporator, the crude product was        purified by flash chromatography. Yield: 6.5 g (25.66 mmol,        63%).

f) 2-(N-Boc-Aminomethyl)-4-methylthiazole-5-thiocarboxamide

-   -   2-(N-Boc-Aminomethyl)-5-cyano-4-methylthiazole (7.5 g, 29.61        mmol) was dissolved in pyridine (30 ml), and triethylamine        (27 ml) was added. The solution was saturated with hydrogen        sulfide at 0° C. and then left to stand at room temperature for        48 h. The solvent was then removed in a rotary evaporator, and        the residue was taken up in ethyl acetate, washed with 20%        strength potassium bisulfate solution and dried over magnesium        sulfate. The solvent was removed in a rotary evaporator, and the        crude product was dissolved in dichloromethane and precipitated        with petroleum ether. The precipitated product was filtered off        with suction and dried in a vacuum oven at 40° C. Yield: 7.1 g        (24.7 mmol, 83%).

g) 5-Amidino-2-(N-Boc-aminomethyl)-4-methylthiazole×HOAc

-   -   2-(N-Boc-Aminomethyl)-4-methylthiazole-5-thiocarboxamide (7.1 g,        24.70 mmol) was dissolved in dichloromethane (40 ml), and        iodomethane (17.5 g, 123.52 mmol) was added. After stirring at        room temperature for 56 h, the solvent was removed in a rotary        evaporator. The residue was dissolved in 10% strength methanolic        ammonium acetate solution (29 ml) and stirred at 40° C. until        the reaction was complete. The solvent was removed in a rotary        evaporator, the residue was extracted by stirring with        dichloromethane, and the resulting solid was filtered off with        suction and washed with dichloromethane. The residue was        dissolved in methanol and converted into the corresponding        acetate using an acetate-loaded ion exchanger. The solvent was        removed in a rotary evaporator and the resulting reddish brown        oil was extracted by stirring with dichloromethane. This        resulted in the product as a colorless solid which was dried in        vacuo at 40° C. Yield: 5.3 g (16.04 mmol, 65%).

h) 5-Amidino-2-aminomethyl-4-methylthiazole×2 HCl

-   -   5-Amidino-2-(N-Boc-aminomethyl)-4-methylthiazole×HOAc (1.6 g,        4.84 mmol) was suspended in dichloromethane (20 ml) and, at room        temperature, 4M hydrochloric acid in 1,4-dioxane (4.84 ml, 19.37        mmol) was added and the mixture was stirred at this temperature        for 3 h. The product was filtered off and washed with        dichloromethane, and dried in vacuo at 40° C.

Yield: 0.73 g (3.00 mmol, 62%).

2-Aminomethyl-5-amidino-4i-trifluoromethylthiazole×2 HCl a) Ethyl2-(N-Boc-aminomethyl)-4-trifluoromethylthiazole-5-carboxylate

-   -   N-Boc-Glycinethioamide (5.0 g, 26.28 mmol) was dissolved in        acetonitrile. (60 ml) and, at 5 to 10° C., a solution of ethyl        2-chloro-4,4,4-trifluoroacetoacetate (6.38 g, 26.28 mmol) was        added dropwise. The mixture was then stirred at 5° C. for 30 min        and at room temperature for 12 h. It was then cooled to 0° C.        and triethylamine (12 ml, 86.77 mmol) was added dropwise. After        stirring at 0° C. for 20 min, the yellowish suspension had        changed to a clear reddish brown solution. Then thionyl chloride        (2.1 ml, 28.89 mmol) was slowly added dropwise at 0° C. Stirring        at 0° C. for 20 min was followed by warming to room temperature        in 1 h. The solvent was removed in a rotary evaporator, and the        residue was taken up in water (100 ml) and extracted several        times with ethyl acetate. The combined organic phases were dried        (Na₂SO₄) and concentrated. The crude product was purified by        chromatography (silica gel, MeOH:DCM=2:98). Yield: 2.2 g (6.4        mmol, 24.5%).

¹H-NMR (270 MHz, DMSO-d₆) δ=1.30 (t, J=6.5 Hz, 3H), 1.45 (s, 9H), 4.35(q, J=6.5 Hz, 2H), 4.45 (d, J=6.5 Hz, 2H), 7.95 (t, J=6.5 Hz, 1H).

b) 2-(N-Boc-Aminomethyl)-4-trifluoromethylthiazole-5-carboxamide

-   -   Ethyl        2-(N-Boc-aminomethyl)-4-trifluoromethylthiazole-5-carboxylate        (15 g, 42.33 mmol) was dissolved in methanol. Ammonia was passed        through the solution at room temperature until the ester was        completely converted into the carboxamide. The solvent was        removed in a rotary evaporator, and the crude product was        purified by flash chromatography. Yield: 4.6 g (14.14 mmol,        33%).

c) 2-(N-Boc-Aminomethyl)-5-cyano-4-trifluoromethylthiazole

-   -   2-(N-Boc-Aminomethyl)-4-trifluoromethylthiazole-5-carboxamide        (4.6 g, 14.14 mmol) was dissolved in dichloromethane (30 ml) and        cooled to −5° C. At this temperature, ethyldiisopropylamine (4.6        g, 35.35 mmol) and a solution of trifluoroacetic anhydride (3.4        g, 16.26 mmol) in dichloromethane (10 ml) were added. The        mixture was then stirred at 0° C. for 2 h. It was washed        successively with saturated sodium bicarbonate solution and 5%        strength citric acid solution. After drying (MgSO₄) the solvent        was removed in a rotary evaporator. The crude product was        extracted by stirring with diethyl ether/petroleum ether. The        supernatant was separated from the oil and concentrated in a        rotary evaporator. Yield: 1.9 g (6.18 mmol, 44%).

d) 2-(N-Boc-Aminomethyl)-4-trifluoromethylthiazole-5-thiocarboxamide

-   -   2-(N-Boc-Aminomethyl)-5-cyano-4-trifluoromethylthiazole (4.6 g,        14.97 mmol) was dissolved in pyridine (20 ml) and, after        addition of triethylamine (24 ml), the solution was saturated        with hydrogen sulfide. After two days at room temperature, the        solvent was removed in a rotary evaporator. The crude product        was taken up in ethyl acetate and washed successively with 20%        strength sodium bisulfate solution and water. After drying        (MgSO₄), the solvent was removed in a rotary evaporator. The        crude product was purified by flash chromatography. Yield: 2.5 g        (7.32 mmol, 49%).

e) 5-Amidino-2-(N-Boc-aminomethyl)-4-trifluoromethylthiazole

-   -   2-(N-Boc-Aminomethyl)-4-trifluoromethylthiazole-5-thiocarboxamide        (2.5 g, 7.32 mmol) was dissolved in dichloromethane (10 ml), and        iodomethane (10.4 g, 73.24 mmol) was added. The mixture was then        stirred at room temperature for 48 h. The solvent was removed in        a rotary evaporator and the residue was taken up in methanol (5        ml), and 10% strength methanolic ammonium acetate solution (8.5        ml, 10.98 mmol) was added. After stirring at room temperature        for 4 days, the solution of the crude product was passed over an        acetate-loaded ion exchanger, and the solvent was removed in a        rotary evaporator. The crude product was purified by flash        chromatography. Yield: 0.8 g (2.08 mmol, 28%).

f) 5-Amidino-2-aminomethyl-4-trifluoromethylthiazole×2 HCl

-   -   5-Amidino-2-(N-Boc-aminomethyl)-4-trifluoromethylthiazole (0.8        g, 2.08 mmol) was dissolved in dichloromethane, and a 4M        solution of hydrochloric acid in 1,4-dioxane (2.1 ml, 4.2 mmol)        was added. After stirring at room temperature for 1 h, the        solvent was removed in a rotary evaporator. The crude product        obtained in this way was employed without further purification        in the following reactions. Yield: 0.6 g (2.0 mmol, 97%).

ESI-MS: 225 (M+H⁺).

5-Aminomethyl-3-methylthiophene-2-carbonitrile a)5-Formyl-3-methylthiophene-2-carbonitrile

-   -   112 ml (179 mmol) of a 1.6 molar solution of n-butyllithium in        n-hexane were added over the course of 20 min to a solution,        cooled to −78° C., of 25.1 ml (179 mmol) of diisopropylamine in        400 ml of tetrahydrofuran. The solution was allowed to reach        −35° C. and was cooled again to −78° C., and a solution of 20.0        g (162 mmol) of 2-cyano-3-methylthiophene in 80 ml of        tetrahydrofuran was slowly added dropwise at this temperature.        The solution became dark red in color. After stirring for 45        min, 63 ml (811 mmol) of dimethylformamide were slowly added        dropwise, and stirring was continued for 30 min. For workup, a        solution of 27 g of citric acid in 160 ml of water was added at        −70° C. Concentration in a rotary evaporator and addition of 540        ml of saturated sodium chloride solution were followed by        extraction three times with 250 ml of diethyl ether each time.        The combined organic extracts were dried over magnesium sulfate.        After filtering off the desiccant, the solvent was distilled off        under waterpump vacuum and the residue was purified by column        chromatography (mobile phase hexane/ethyl acetate 4/1). 23 g        (94%) of the title compound were obtained.

¹H-NMR (270 MHz, DMSO-d₆): δ=2.4 (s, 3H), 8.0 (s, 1H), 9.8 (s, 1H).

b) 5-Hydroxymethyl-3-methylthiophene-2-carbonitrile

-   -   5.75 g (152 mmol) of sodium borohydride were added in portions        to a solution of 23 g (152 mmol) of        5-formyl-3-methylthiophene-2-carbonitrile in 300 ml of absolute        ethanol at room temperature. The reaction mixture was stirred        for 5 minutes, concentrated under waterpump vacuum, taken up in        ethyl acetate and extracted with 5% strength citric acid        solution and with saturated sodium chloride solution, the        organic phase was dried over magnesium sulfate, the desiccant        was filtered off and the solvent was distilled off under        waterpump vacuum at room temperature. This resulted in 24 g of        the title compound as a dark red oil which still contained        solvent and was employed without further purification in the        following reactions.

¹H-NMR (270 MHz, DMSO-d₆): δ=2.4 (s, 3H), 4.7 (m, 2H), 5.9 (m, 1H), 7.0(s, 1H).

c) 5-Bromomethyl-3-methylthiophene-2-carbonitrile

-   -   44 g (167 mmol) of triphenylphosphine were added to a solution        of 24 g (152 mmol) of        5-hydroxymethyl-3-methylthiophene-2-carbonitrile in 180 ml of        tetrahydrofuran. A solution of 55 g (167 mmol) of        tetrabromomethane in 100 ml of tetrahydrofuran was then added.        The reaction mixture was stirred at room temperature for 90 min.        It was then concentrated in a rotary evaporator under waterpump        vacuum, and the residue was purified by column chromatography        (mobile phase hexane:ethyl acetate 8:2). 34 g of the title        compound which still contained a little solvent were obtained.

¹H-NMR (270 MHz, DMSO-d₆): δ=2.4 (s, 3H), 5.0 (s, 2H), 7.3 (s, 1H).

d)5-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-3-methylthiophene-2-carbonitrile

-   -   5.0 g (167 mmol) of sodium hydride (80% suspension in mineral        oil) were added in portions to a solution, cooled to 0° C., of        33.8 g (152 mmol) of        5-bromomethyl-3-methylthiophene-2-carbonitrile in 255 ml of        tetrahydrofuran. Then a solution of 36.4 g (167 mmol) of        di-tert-butyl iminodicarboxylate in 255 ml of tetrahydrofuran        was added dropwise, during which the temperature did not exceed        5° C. The mixture was allowed to reach room temperature and was        stirred overnight. It was then heated at 35° C. for 3 hours to        complete the reaction and, after cooling to room temperature,        510 ml of a saturated ammonium chloride solution were slowly        added. The solvent was distilled off under waterpump vacuum, the        residue was extracted several times with ethyl acetate, and the        combined organic phases were washed with saturated sodium        chloride solution, dried over magnesium sulfate and concentrated        in a rotary evaporator. 57.6 g of an oily residue which still        contained di-tert-butyl iminodicarboxylate were obtained and        were employed as crude product in the following reaction.

¹H-NMR (270 MHz, DMSO-d₆): δ=1.45 (s, 18H), 2.35 (s, 3H), 4.85 (s, 2H),7.05 (s, 1H).

e) 5-Aminomethyl-3-methylthiophene-2-carbonitrile hydrochloride

-   -   52.6 g of        5-[N,N-bis(tert-butoxycarbonyl)aminomethyl]-3-methylthiophene-2-carbonitrile        (crude product from d), maximum 139 mmol) were dissolved in 950        ml of ethyl acetate and cooled to 0° C. On saturation with        gaseous hydrogen chloride a white precipitate separated out        after 10 min. After stirring at room temperature for two hours        and at 30° C. for one hour, the resulting suspension was        concentrated in a rotary evaporator, the residue was extracted        by stirring with diethyl ether, the solvent was removed by        filtration, and the solid residue was dried in vacuo at room        temperature. 24.7 g (94%) of the title compound were obtained as        a white powder.

¹H-NMR (270 MHz, DMSO-d₆): δ=2.4 (s, 3H), 4.25 (s, 2H), 7.3 (s, 1H),8.8–9.0 (bs, 3H). ¹³C-NMR (DMSO-d₆): 15.0 (CH₃), 36.4 (CH₂), 104.8(C-2), 113.8 (CN), 131.5 (C-4), 142.8 (C-5), 149.6 (C-3).

5-Aminomethyl-3-chlorothiophene-2-carbonitrile hydrochloride

This compound was prepared in analogy to5-aminomethyl-3-methylthiophene-2-carbonitrile, preparing the3-chloro-2-cyanothiophene used by dehydration of3-chlorothiophene-2-carboxamide with trifluoroacetic anhydride.

2-Aminomethyl-3-methylthiophene-4-thiocarboxamide a) Ethyl2-amino-3-cyano-4-methylthiophene-5-carboxylate

-   -   Ethyl 2-amino-3-cyano-4-methylthiophene-5-carboxylate was        synthesized in accordance with “Organikum”, 19^(th) edition, Dt.        Verlag der Wissenschaften, Leipzig, Heidelberg, Berlin, 1993,        chapter 6, pages 374–375, starting from 130 g (1.0 mol) of ethyl        acetoacetate, 66 g (1.0 mol) of malononitrile, 32 g (1.0 mol) of        sulfur and 80 g (0.92 mol) of morpholine.

¹H-NMR (270 MHz, DMSO-d₆): δ=1.25 (t, 3H), 2.3 (s, 3H), 4.2 (q, 2H), 7.9(bs, 2H).

b) Ethyl 4-cyano-3-methylthiophene-2-carboxylate

-   -   A solution of 20.5 g (97.5 mmol) of ethyl        2-amino-3-cyano-4-methylthiophene-5-carboxylate in 600 ml of a        1:1 mixture of acetonitrile and dimethylformamide was cooled to        5° C., and 15.7 g (146 mmol) of tert-butyl nitrite were added        dropwise, during which the reaction mixture became hot and        vigorous evolution of gas started. After stirring at room        temperature for seven hours and concentrating in a rotary        evaporator and under high vacuum, the residue was purified by        column chromatography (mobile phase dichloromethane) to result        in 9.1 g (48%) of the required compound as a yellow oil.

¹H-NMR (270 MHz, DMSO-d₆): δ=1.3 (t, 3H), 2.55 (s, 3H), 4.3 (q, 2H), 8.8(s, 1H).)

c) 2-Hydroxymethyl-3-methylthiophene-4-carbonitrile

-   -   2.44 g (64 mmol) of lithium aluminum hydride were added in        portions to a solution of 25.1 g (129 mmol) of ethyl        4-cyano-3-methylthiophene-2-carboxylate in 400 ml of        tetrahydrofuran at 0° C. The mixture was stirred at room        temperature for five hours, excess reducing agent was destroyed        by adding 0.5N hydrochloric acid, and the reaction mixture was        concentrated under waterpump vacuum, diluted with water and        extracted three times with ethyl acetate. The combined organic        phases were then washed once each with 0.5N hydrochloric acid        and saturated sodium chloride solution. The organic phase was        dried over magnesium sulfate, the desiccant was filtered off,        and the solvent was distilled off under waterpump vacuum at room        temperature. The residue was purified by column chromatography        (mobile phase dichloromethane/methanol 95:5) to result in 16.1 g        (83%) of the required compound as a pale yellow oil.

¹H-NMR (270 MHz, DMSO-d₆): δ=2.2 (s, 3H), 4.6 (d, 2H), 5.7 (m, 1H), 8.35(s, 1H).

d) 2-Bromomethyl-3-methylthiophene-4-carbonitrile

-   -   30 g (115 mmol) of triphenylphosphine were added to a solution        of 16 g (104 mmol) of        2-hydroxymethyl-3-methylthiophene-4-carbonitrile in 300 ml of        tetrahydrofuran at 5° C. A solution of 38 g (115 mmol) of        tetrabromomethane in 100 ml of tetrahydrofuran was then added.        The reaction mixture was stirred at room temperature overnight.        It was then concentrated in a rotary evaporator under waterpump        vacuum, and the residue was purified by column chromatography        (mobile phase petroleum ether: dichloromethane 1:1). 17 g (76%)        of the title compound were obtained as a yellow oil.

¹H-NMR (270 MHz, DMSO-d₆): δ=2.25 (s, 3H), 5.0 (s, 2H), 8.5 (s, 1H).

e)2-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-3-methylthiophene-3-carbonitrile

-   -   3.5 g (103 mmol) of sodium hydride (oil-free) were added in        portions to a solution, cooled to 0° C., of 17.2 g (79.5 mmol)        of 2-bromomethyl-3-methylthiophene-4-carbonitrile in 250 ml of        tetrahydrofuran. A solution of 22.5 g (103 mmol) of        di-tert-butyl iminodicarboxylate in 100 ml of tetrahydrofuran        was then added dropwise, during which the temperature did not        exceed 5° C. The mixture was allowed to warm to room temperature        and was stirred for two hours. 400 ml of a saturated ammonium        chloride solution were slowly added. The solvent was distilled        off under waterpump vacuum, and the residue was diluted with a        little water and extracted three times with ethyl acetate. The        combined organic phases were washed with saturated ammonium        chloride solution and with saturated sodium chloride solution,        dried over magnesium sulfate and concentrated in a rotary        evaporator. 28 g of an oil which still contained di-tert-butyl        iminodicarboxylate were obtained and were employed as crude        product in the following reaction.

¹H-NMR (270 MHz, DMSO-d₆): δ=1.4 (s, 9H), 1.45 (s, 9H), 2.3 (s, 3H), 4.8(s, 2H), 8.4 (s, 1H).

f)2-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-3-methylthiophene-4-thiocarboxamide

-   -   The crude product (max. 79 mmol) obtained from e) was dissolved        in 280 ml of pyridine and 140 ml of triethylamine and saturated        with hydrogen sulfide at room temperature. The previously yellow        solution became green. It was stirred at room temperature        overnight. To complete the reaction, hydrogen sulfide was passed        in for a further 15 min, and the mixture was stirred at room        temperature for two hours. A stream of nitrogen was used to        drive out excess hydrogen sulfide through a scrubbing tower. The        reaction mixture was then concentrated in a rotary evaporator,        taken up in ethyl acetate, washed several times with 20%        strength sodium bisulfate solution, dried over magnesium sulfate        and concentrated in a rotary evaporator. This resulted in 27 g        of a pale yellow solid foam which was employed without further        purification in the following reaction.

¹H-NMR (270 MHz, DMSO-d₆): δ=1.4 (s, 18H), 2.15 (s, 3H), 4.8 (s, 2H),7.5 (s, 1H), 9.3 (bs, 1H), 9.75 (bs, 1H).

g) 2-Aminomethyl-3-methylthiophene-4-thiocarboxamide hydrochloride

-   -   27 g of        2-[N,N-bis(tert-butoxycarbonyl)aminomethyl]-3-methylthiophene-4-thiocarboxamide        (crude product from f), maximum 70 mmol) were dissolved in 400        ml of ethyl acetate and cooled to 0° C. On saturation with        gaseous hydrogen chloride, a white precipitate separated out        after 10 min. After stirring at room temperature for two hours,        the precipitate was filtered off and washed with ethyl acetate,        and the solid residue was dried at room temperature in vacuo.        13.6 g (87%) of the title compound were obtained as a white        powder.

EI-MS: M⁺=186.

2-Aminomethyl-3-chlorothiophene-4-thiocarboxamide a)2-Formyl-3-chlorothiophene-4-carbonitrile

-   -   35 g (325 mmol) of tert-butyl nitrite were added dropwise to a        solution of 53.0 g (250 mmol) of        2-amino-4-chloro-5-formylthiophene-3-carbonitrile (the        preparation of this compound is described in the patent        DB 3738910) in 600 ml of a 1:1 mixture of acetonitrile and        dimethylformamide at room temperature, during which the reaction        mixture warmed from 20° C. to 37° C. and vigorous evolution of        gas started. After cooling to 25° C. and stirring at room        temperature for seven hours, the black solution was concentrated        in a rotary evaporator and under high vacuum, and the residue        was purified by column chromatography (mobile phase        dichloromethane) to result in 29 g (68%) of the required        compound as a yellow oil.

¹H-NMR (270 MHz, DMSO-d₆): δ=9.1 (S, 1H), 10.0 (s, 1H).

b) 2-Hydroxymethyl-3-chlorothiophene-4-carbonitrile

-   -   6.3 g (166 mmol) of sodium borohydride were added in portions to        a solution of 28.5 g (166 mmol) of        2-formyl-3-chlorothiophene-4-carbonitrile in 400 ml of absolute        methanol at 5° C. The reaction mixture became slightly warm and        dark red in color. Vigorous evolution of gas was observed. After        ten minutes, the reaction mixture was concentrated under        waterpump vacuum, taken up in 200 ml of ethyl acetate, extracted        with 200 ml of 1M hydrochloric acid, and washed twice with 250        ml of water each time and with saturated sodium chloride        solution, the organic phase was dried over magnesium sulfate,        the desiccant was filtered off, and the solvent was distilled        off under waterpump vacuum at room temperature. 22 g (76%) of        the title compound were obtained as a dark red oil which was        employed without further purification in the following        reactions.

¹H-NMR (270 MHz, DMSO-d₆): δ=4.65 (bs, 1H), 5.95 (t, 2H), 8.6 (s, 1H).

c) 2-Bromomethyl-3-chlorothiophene-4-carbonitrile

-   -   36.1 g (137 mmol) of triphenylphosphine were added to a solution        of 21.7 g (125 mmol) of        2-hydroxymethyl-3-chlorothiophene-4-carbonitrile in 250 ml of        tetrahydrofuran at 5° C. A solution of 45.6 g (137 mmol) of        tetrabromomethane in 100 ml of tetrahydrofuran was then added.        The mixture was stirred at room temperature overnight. The        precipitate was filtered off, the filtrate was concentrated in a        rotary evaporator under waterpump vacuum, and the residue was        purified by column chromatography (mobile phase petroleum ether:        dichloromethane 1:1). 26.0 g (88%) of the title compound were        obtained as an oil.

¹H-NMR (270 MHz, DMSO-d₆): δ=4.95 (s, 2H), 8.8 (s, 1H).

d)2-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-3-chlorothiophene-4-carbonitrile

-   -   6.9 g (159 mmol) of sodium hydride (oil-free) were added in        portions to a solution, cooled to 0° C., of 25.0 g (106 mmol) of        2-bromomethyl-3-chlorothiophene-4-carbonitrile in 300 ml of        tetrahydrofuran. A solution of 34.4 g (159 mmol) of        di-tert-butyl iminodicarboxylate in 100 ml of tetrahydrofuran        was then added dropwise, during which the temperature did not        exceed 5° C. The mixture was allowed to warm to room temperature        and was stirred for two hours. 300 ml of a saturated ammonium        chloride solution were slowly added. The solvent was distilled        off under waterpump vacuum, and the residue was diluted with a        little water and extracted three times with ethyl acetate. The        combined organic phases were washed with saturated ammonium        chloride solution and with saturated sodium chloride solution,        dried over magnesium sulfate and concentrated in a rotary        evaporator. 51.3 g of an oil which still contained di-tert-butyl        iminodicarboxylate and solvent residue were obtained and were        employed as crude product in the following reaction.

¹H-NMR (270 MHz, DMSO-d₆): δ=1.4 (s, 9H), 1.45 (s, 9H), 4.8 (s, 2H),8.65 (s, 1H).

e)2-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-3-methylthiophene-4-thiocarboxamide

-   -   Part of the crude product obtained from d) (39.4 g, max. 106        mmol) was dissolved in 400 ml of pyridine and 40 ml of        triethylamine and, at room temperature, saturated with hydrogen        sulfide. The previously yellow solution became green. It was        stirred at room temperature overnight. A stream of nitrogen was        used to drive out excess hydrogen sulfide through a scrubbing        tower. The reaction mixture was then poured into ice-cold, 20%        strength sodium bisulfate solution and extracted three times        with ethyl acetate. The organic phase was subsequently washed        several times with 20% strength sodium bisulfate solution, dried        over magnesium sulfate and concentrated in a rotary evaporator.        This resulted in 49.0 g of a solvent-containing residue which        was employed without further purification in the following        reaction.

¹H-NMR (270 MHz, DMSO-d₆): δ=1.4, 1.45 (s, 18H), 4.8 (s, 2H), 7.75 (s,1H), 9.4 (bs, 1H), 10.0 (bs, 1H).

f) 2-Aminomethyl-3-chlorothiophene-4-thiocarboxamide hydrochloride

-   -   38.0 g of the crude product from e), maximum 93 mmol, were        dissolved in 400 ml of ethyl acetate and cooled to 0° C. On        saturation with hydrogen chloride gas a white precipitate        separated out after 10 min. Since conversion was still        incomplete, 200 ml of ethyl acetate were added and the solution        was saturated again with hydrogen chloride gas and stirred at        room temperature overnight. The precipitate was filtered off,        washed with petroleum ether and dried at room temperature in        vacuo. 21.1 g of the title compound were obtained as a white        powder which contained ammonium chloride as impurity.

EI-MS: M⁺=206.

5-Aminomethyl-2-cyanofuran a) 5-Cyanofuran-2-carbaldehyde

-   -   165 ml (264 mmol) of a 1.6 molar solution of n-butyllithium in        n-hexane were added over the course of 20 min to a solution of        26.7 g (264 mmol) of diisopropylamine in 600 ml of        tetrahydrofuran cooled to −78° C. The solution was allowed to        reach −20° C., again cooled to −75° C. and, at this temperature        a solution of 22.3 g (240 mmol) of 2-cyanofuran in 100 ml of        tetrahydrofuran was slowly added dropwise. After stirring for 30        min, 93 ml of dimethylformamide were slowly added dropwise, and        the mixture was stirred for a further 30 min. For workup, a        soluiton of 40 g of citric acid in 200 ml of water was added at        −70° C. After concentration in a rotary evaporator, 600 ml of        saturated sodium chloride solution were added, and the mixture        was extracted three times with 200 ml of diethyl ether each        time. The combined organic extracts were dried over magnesium        sulfate. The desiccant was filtered off and then the solvent was        distilled off under waterpump vacuum, and the residue was        purified by column chromatography (mobile phase        dichloromethane). The eluate was concentrated and the residue        was subjected to steam distillation (boiling range of the        azeotrope with water: 60 to 65° C. at p=0.1 mm Hg). Extraction        of the distillate with diethyl ether, drying of the organic        phase and concentration of the solution resulted in 10.6 g (88        mmol, 36%) of the title compound.

¹H-NMR (270 MHz, d₆-DMSO): δ=7.7 (d, 1H), 7.8 (d, 1H), 9.75 (s, 1H).

b) 5-Hydroxymethyl-2-cyanofuran

-   -   2.34 g (62 mmol) of sodium borohydride were added in portions to        a solution of 30 g (0.25 mol) of 5-cyanofuran-2-carbaldehyde in        500 ml of absolute ethanol at −30° C. The solution was stirred        at −30° C. for two hours and, while cooling, was adjusted to pH        7 with a 5% strength citric acid solution in water. The reaction        mixture was concentrated under waterpump vacuum, saturated        sodium chloride solution was added to the residue, the mixture        was extracted several times with 150 ml of diethyl ether each        time, the combined organic phases were dried over magnesium        sulfate, the desiccant was filtered off, and the solvent was        distilled off under waterpump vacuum at room temperature. This        resulted in 27 g (22 mmol, 88%) of the title compound as a dark        red oil, which was employed without further purification in the        following reactions.

¹H-NMR (250 MHz, d₆-DMSO): δ=4.4 (m, 2H), 5.6 (bs, 1H), 6.6 (d, 1H), 7.5(d, 1H).

c) 5-Bromomethyl-2-cyanofuran

-   -   38 g (145 mmol) of triphenylphosphine were added to a solution        of 15 g (121 mol) of 5-hydroxymethyl-2-cyanofuran in 250 ml of        tetrahydrofuran. The mixture was cooled to −10° C., and a        solution of 48 g (145 mmol) of tetrabromomethane in 100 ml of        tetrahydrofuran was added. The mixture was allowed to warm to        room temperature and was stirred at this temperature for three        hours. The reaction mixture was concentrated in a rotary        evaporator under waterpump vacuum, and the residue was purified        by column chromatography (mobile phase petroleum ether:        dichloromethane 1:1, R_(f)=0.5). 11.5 g of the title compound        were obtained.

¹H-NMR (250 MHz, d₆-DMSO): δ=4.8 (m, 2H), 6.7 (d, 1H), 7.7 (d, 1H).

d) 5-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-2-cyanofuran

-   -   4.0 g (135 mmol) of sodium hydride (80% suspension in mineral        oil) were added in portions to a solution of 22.9 g (123 mmol)        of 5-bromomethyl-2-cyanofuran in 400 ml of tetrahydrofuran        cooled to 0° C. Then a solution of 29.4 g (135 mmol) of        di-tert-butyl iminodicarboxylate in 200 ml of tetrahydrofuran        was added dropwise, during which the temperature did not exceed        5° C. The mixture was allowed to warm to room temperature and        was stirred overnight. Since conversion was incomplete (TLC        check), a total of 1.2 g of sodium hydride was added in three        portions over a period of 9 hours. To complete the conversion,        the mixture was then heated at 35° C. for three hours and, after        allowing to cool to room temperature, 600 ml of a saturated        ammonium chloride solution were slowly added. The solvent was        distilled off under waterpump vacuum, the residue was extracted        several times with ethyl acetate, and the combined organic        phases were washed with saturated sodium chloride solution,        dried over magnesium sulfate and concentrated in a rotary        evaporator. 37.3 g of an oily residue which still contained        di-tert-butyl iminodicarboxylate were obtained and were employed        as crude product in the following reaction.

¹H-NMR (250 MHz, d₆-DMSO): δ=1.40, 1.45 (s, 18H), 4.75 (s, 2H), 6.55 (d,1H), 7.55 (d, 1H).

e) 5-Aminomethyl-2-cyanofuran hydrochloride

-   -   37.3 g of        5-[N,N-bis(tert-butoxycarbonyl)aminomethyl]-2-cyanofuran (crude        product from d), maximum 123 mmol) were dissolved in 600 ml of        ethyl acetate and cooled to 0° C. The solution was saturated        with hydrogen chloride gas, a white precipitate separating out        after 30 min. The mixture was allowed to reach room temperature        and was stirred overnight, and then the resulting suspension was        concentrated in a rotary evaporator, the residue was extracted        by stirring with diethyl ether, the solvent was removed by        filtration, and the solid residue was dried at room temperture        in vacuo. 15.1 g (77% yield over two stages) of the title        compound were obtained as a pale ochre powder.

¹H-NMR (250 MHz, d₆-DMSO): δ=4.15 (bs, 2H), 6.85 (d, 1H), 7.65 (d, 1H),8.8–9.0 (bs, 3H).

2-Aminomethyl-4-cyanofuran hydrochloride a)2-[N,N-Bis(tert-butoxycarbonyl)aminomethyl]-4-cyanofuran

-   -   A solution, cooled to 0° C., of 20.5 g (0.11 mol) of        5-bromomethyl-3-cyanofuran (L. M. Pevzner, V. M. Ignat'ev, B. I.        Ionin, Russ. J. of Gen. Chem. 1994, 64, 2, 125–128) in 50 ml of        tetrahydrofuran was added over the course of 30 min to a stirred        suspension of 4.8 g (0.12 mol) of sodium hydride (60% dispersion        in mineral oil) in 30 ml of tetrahydrofuran at 0° C. A solution        of 26.2 g (121 mmol) of di-tert-butyl iminodicarboxylate in 50        ml of tetrahydrofuran was then added dropwise, during which the        temperature did not exceed 5° C. The mixture was stirred at 5 to        10° C. for three hours, allowed to warm to room temperature and        stirred overnight. 150 ml of a saturated ammonium chloride        solution were slowly added. The solvent was distilled off under        waterpump vacuum, the residue was extracted four times with 60        ml of ethyl acetate each time, and the combined organic phases        were washed twice with saturated sodium chloride solution, dried        over magnesium sulfate and concentrated in a rotary evaporator.        Drying at room temperture in vacuo (1 mm Hg) for three hours        resulted in 33.2 g of a dark syrup which still contained        di-tert-butyl iminodicarboxylate and was employed as crude        product in the following reaction.

¹H-NMR (250 MHz, d₆-DMSO): δ=1.40, 1.45 (s, 18H), 4.70 (s, 2H), 6.70 (s,1H), 8.6 (s, 1H).

b) 2-Aminomethyl-4-cyanofuran hydrochloride

-   -   12.89 g of        2-[N,N-bis(tert-butoxycarbonyl)aminomethyl]-4-cyanofuran (crude        product from a) were dissolved in 80 ml of ethyl acetate and        cooled to −10° C. On saturation with hydrogen chloride gas a        white precipitate separated out after 15 min. The mixture was        allowed to reach room temperature and was stirred for two hours,        the resulting suspension was then concentrated in a rotary        evaporator, the residue (7 g) was extracted by stirring with        diethyl ether, the solvent was removed by filtration, and the        solid residue was dried at room temperature in vacuo. 5 g (79%)        of the title compound were obtained as a pale ochre powder.

¹H-NMR (250 MHz, d₆-DMSO): δ=4.15 (bs, 2H), 7.0 (s, 1H), 8.6–8.9 (m,4H).

5-Aminomethyl-3-cyano-1,2,4-oxadiazole hydrochloride a)N-Boc-5-Aminomethyl-3-cyano-1,2,4-oxadiazole

-   -   Ethyl N-Boc-5-aminomethyl-1,2,4-oxadiazole-3-carboxylate (S.        Borg et al. J. Org. Chem. 1995, 60, 3112–20) was dissolved in        methanol (50 ml). Ammonia was passed into this solution at        −10° C. to RT until reaction was complete. The solvent was        removed in a rotary evaporator. The crude product obtained in        this way was dissolved in dichloromethane (70 ml) and, at −5°        C., diisopropylethylamine (2.9 ml, 16.55 mmol) was added. Then        trifluoroacetic anhydride (1.06 ml, 7.61 mmol) dissolved in        dichloromethane (10 ml), was added dropwise. The mixture was        stirred at 0° C. for 1.5 h and then diluted with        dichloromethane, washed 2× with saturated sodium bicarbonate        solution, 2× with 5% strength citric acid solution and 1× with        saturated sodium chloride solution and then dried over sodium        sulfate. The solvent was removed in a rotary evaporator and the        crude product was purified by chromatography (silica gel,        dichloromethane: methanol=97.5:2.5). Yield: 1.2 g (80%).

b) 5-Aminomethyl-3-cyano-1,2,4-oxadiazole hydrochloride

-   -   The product obtained in a) (0.9 g, 4.0 mmol) was dissolved in        dichloromethane (45 ml) and, at RT, 4 M hydrochloric acid in        dioxane (3.9 ml, 15.61 mmol) was added. After stirring at RT for        16 h, the solvent was removed in a rotary evaporator. Yield: 645        mg (100%).

¹H-NMR (DMSO-d₆) δ=4.6 (s, 2H), 9.2 (s, 3H).

Example 1N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-methoxycarbonyl)amidino-5-thienylmethylamide hydrochloride a)3,4-Dehydroproline 2-cyano-5-thienylmethylamide

-   -   Boc-3,4-Dehydroproline (5 g, 23.4 mmol) and        5-aminomethyl-2-cyanothiophene hydrochloride (4.5 g, 25.8 mmol;        WO 95/23609) were dissolved in dichloromethane (25 ml) and, at        0° C., ethyldiisopropylamine (28 ml, 163.8 mmol) and a 50%        strength solution of propanephosphonic anhydride in ethyl        acetate (24.8 ml, 117 mmol) were added. The mixture was stirred        at 0° C. for 1 h and then warmed to RT and stirred at RT for        12 h. The reaction mixture was diluted with dichloromethane and        washed with sodium bisulfate solution (4×), sodium bicarbonate        solution (3×) and saturated sodium chloride solution (1×). After        drying over sodium sulfate and removal of the desiccant by        filtration, the solvent was distilled off under waterpump        vacuum. To eliminate the Boc group, the residue was mixed with        HCl in dichloromethane (95 ml), stirred at RT, evaporated to        dryness, codistilled twice with dichloromethane, again        concentrated and purified by column chromatography. 6.6 g of the        required product, which still contained a small amount of        solvent, were obtained.

b)N-(tert-butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline2-cyano-5-thienylmethylamide

-   -   t-BuO₂C—CH₂-(Boc)-(D)-Chg-OH (6.5 g, 17.5 mmol; WO 9806741) and        H-Pyr-NH—CH₂-5-(2-CN)-thioph hydrochloride (4.72 g, 17.5 mmol)        were suspended in dichloromethane (90 ml), and        ethyldiisopropylamine (11.3 g, 87.5 mmol) was added, resulting        in a clear, pale reddish solution. The reaction mixture was        cooled to about 5° C. and a 50% strength solution of        propanephosphonic anhydride in ethyl acetate (18 ml) was added        dropwise. Stirring at RT overnight was followed by dilution with        dichloromethane (100 ml) and washing with dilute sodium        bisulfate solution (3×), saturated sodium bicarbonate solution        (2×) and water (1×). Drying over sodium sulfate and removal of        the desiccant was followed by removal of the solvent by        distillation under waterpump vacuum. 11.15 g of a pale reddish        brown oil were obtained.

c)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline2-aminothiocarbonyl-5-thienylmethylamide

-   -   The product obtained in b),        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-CN)-thioph, was        dissolved in pyridine (68 ml) and triethylamine (11.5 ml). The        reaction mixture was cooled to 0° C. and saturated with hydrogen        sulfide (the solution became green). The reaction solution was        left to stand at RT overnight. The excess hydrogen sulfide was        displaced by nitrogen, and the solvent was distilled off under        waterpump vacuum. The residue was dissolved in diethyl ether        (500 ml) and washed with dilute sodium bisulfate solution (3×),        saturated sodium bicarbonate solution (2×) and water (1×). After        drying over sodium sulfate, the solvent was distilled off under        waterpump vacuum. The viscous yellow crude product (10.92 g) was        employed without further purification in the next stage.

d)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline2-methylthio(imino)methyl-5-thienylmethylamide hydroiodide

-   -   The crude product obtained in c),        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-CSNH₂)-thioph, was        dissolved in dichloromethane (115 ml), and methyl iodide (14.99        g, 105.6 mmol) was added. After stirring at RT over the weekend,        the solvent was removed by distillation under waterpump vacuum.        12.6 g of a yellowish solid foam were obtained.

e)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline2-amidino-5-thienylmethylamide acetate

-   -   The crude product obtained in d),        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(SCH₃))-thioph×HI,        was mixed with 25.5 ml of a 10% strength solution of ammonium        acetate in methanol (2.55 g of ammonium acetate, 38.12 mmol).        Since precursor was still present according to TLC after        stirring at RT overnight, a further 3.0 ml of a 10% strength        solution of ammonium acetate in methanol was added and the        mixture was stirred at RT overnight. The solvent was then        removed by distillation under waterpump vacuum, the residue was        taken up in dichloromethane, the salts were filtered off with        suction, and the filtrate was concentrated, resulting in 13.3 g        of crude product in the form of a yellow solid foam. The product        was dissolved in methanol and converted into the corresponding        acetate salt on an ion exchanger (Fluka: acetate on polymeric        support, 3.0 mmol of acetate per g).

f)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline2-amidino-5-thienylmethylamide

-   -   The crude product obtained in e),        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(NH₂))-thioph×CH₃COOH,        was dissolved in methylene chloride, concentrated ammonia        solution was added (pH 11), the aqueous phase was extracted        several times with methylene chloride, and the combined organic        phases were dried over magnesium sulfate and concentrated in        vacuo. The product was obtained as a white solid.

g)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-methoxycarbonyl)amidino-5-thienylmethylamide

-   -   The crude product obtained in f),        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH-CH₂-5-(2-C═NH(NH₂))-thioph (1.4        g, 2.32 mmol), were dissolved in 50 ml of methylene chloride        and, after addition of diisopropylamine (3.0 g, 23.2 mmol) and        then, while cooling with a waterbath, dropwise methyl        chloroformate (0.24 g, 2.55 mmol) in 5 ml of methylene chloride,        the mixture was stirred at room temperature for 1 h. The residue        after concentration in vacuo was mixed with ether, water and 5%        strength citric acid (pH 5) and extracted, and the ether phase        once again washed with acid (pH 3), dried over magnesium sulfate        and concentrated in vacuo. 1.7 g of the product were obtained as        a colorless foam.)

h) N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-methoxycarbonyl)amidino-5-thienylmethylamide hydrochloride

-   -   The crude product obtained in g),        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH -5-(2=NH(NH—COOCH₃))-thioph        (1.7 g, max. 2.3 mmol), was dissolved in a mixture of 45 ml of        methylene chloride, 20 ml of dioxane and 45 ml of 4N        hydrochloric acid in dioxane and stirred overnight with        exclusion of moisture. The reaction solution was concentrated in        vacuo, and the residue was codistilled with ether several times        and subsequently extracted by stirring with ether. After drying        in vacuo, 1.3 g of the title compound were obtained as a white        solid product. Neutral aqueous solutions of the product are        distinctly more stable than acidic solutions because the        acylated amidine function is hydrolyzed under these conditions.        FAB-MS (M+H⁺): 506

Example 2N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-isobutyloxycarbonyl)amidino-5-thienylmethylamide hydrochloride:FAB-MS (M+H⁺): 548

Preparation took place in analogy to Example 1 by reactingt-BuO₂C—H₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(NH₂))-thioph with isobutylchloroformate and subsequently eliminating protective groups.

Example 3N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-n-hexyloxycarbonyl)amidino-5-thienylmethylamide hydrochloride:FAB-MS (M+H⁺): 576

Preparation took place in analogy to Example 1 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(NH₂))-thioph with hexylchloroformate and subsequently eliminating protective groups.

Example 4N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-allyloxycarbonyl)amidino-5-thienylmethylamide hydrochloride: FAB-MS(M+H⁺): 532

Preparation took place in analogy to Example 1 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH-CH₂-5-(2-C═NH(NH₂))-thioph with allylchloroformate and subsequently eliminating protective groups.

Example 5N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-benzyloxycarbonyl)amidino-5-thienylmethylamide hydrochloride:FAB-MS (M+H⁺): 582

Preparation took place in analogy to Example 1 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(NH₂))-thioph with benzylchloroformate and subsequently eliminating protective groups.

Example 6N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-methoxyethoxycarbonyl)amidino-5-thienylmethylamide hydrochloride:FAB-MS (M+H⁺): 550

Preparation took place in analogy to Example 1 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(NH₂))-thioph withmethoxyethyl chloroformate and subsequently eliminating protectivegroups.

Example 7N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-methoxyethoxyethoxycarbonyl)amidino-5-thienylmethylamidehydrochloride: FAB-MS (M+H⁺): 594

Preparation took place in analogy to Example 1 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(NH₂))-thioph withmethoxyethoxyethyl chloroformate and subsequently eliminating protectivegroups.

Example 8N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-methoxyamidino)-5-thienylmethylamide hydrochloride a)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline2-(N-methoxyamidino)-5-thienylmethylamide

-   -   Methoxylamine hydrochloride (0.7 g, 8.38 mmol) was dissolved in        50 ml of methanol and converted into the corresponding acetate        salt on an ion exchanger (Fluka: acetate on polymeric support,        3.0 mmol of acetate per g).        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(SCH₃))-thioph×HI        (3.0 g, 4.0 mmol; see Example 1d) was added to this methanolic        solution, and the reaction mixture was stirred at 50° C. for 15        min (TLC check (methylene chloride/acetone: 9/1)). The residue        after concentration in vacuo was purified by chromatography on        silica gel, it being possible to isolate 1.0 g of the required        product as a pale yellow solid.

b) N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3.4-dehydroproline2-(N-methoxyamidino)-5-thienylmethylamide hydrochloride

-   -   The product obtained in a),        t-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(NHOCH₃))-thioph        (0.9 g, 1.42 mmol), was stirred in a mixture of 10 ml of        methylene chloride and 5 ml of 5 N hydrochloric acid solution in        ether at room temperature with exclusion of moisture for 24 h,        and then 60 ml of ether were added and the precipitated solid        was filtered off. The latter was dissolved in 20 ml of water,        and the aqueous phase was extracted 3 times with ethyl acetate        and freeze dried. 0.7 g of the title compound was obtained as a        white powder.

FAB-MS (M+H⁺): 478

Example 9N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3.4-dehydroproline2-(N-isobutyloxyamidino)-5-thienylmethylamide hydrochloride: FAB-MS(M+H⁺): 520

Preparation took place in analogy to Example 8 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(SCH₃))-thioph×HI withO-isobutylhydroxylamine and subsequently eliminating protective groups.

Example 10N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3.4-dehydroproline2-(N-(p-methylbenzyloxy)amidino)-5-thienylmethylamide hydrochloride:FAB-MS (M+H⁺): 568

Preparation took place in analogy to Example 8 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(SCH₃))-thioph×HI withO-(p-methylbenzyl)hydroxylamine and subsequently eliminating protectivegroups.

Example 11N-(Ethoxycarbonylmethyl)-(D)-cyclohexylglycyl-3.4-dehydroproline2-(N-(p-methylbenzyloxy)amidino)-5-thienylmethylamide hydrochloride:FAB-MS (M+H⁺): 596

Preparation took place in analogy to Example 8 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(SCH₃))-thioph×HI withO-(p-methylbenzyl)hydroxylamine and subsequently eliminating protectivegroups in ethanol, there being simultaneous esterification to give theethyl ester.

Example 12N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3.4-dehydroproline2-hydroxyamidino-5-thienylmethylamide hydrochloride

FAB-MS (M+H⁺): 464

Preparation took place in analogy to Example 8 by reactingt-BuO₂C—CH₂-(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(2-C═NH(SCH₃))-thioph×HI withhydroxylamine hydrochloride in methylene chloride with the aid ofdiisopropylethylamine as base. The protective groups were eliminated in2N aqueous hydrochloric acid at 60° C. within 35 min.

Example 13N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3.4-dehydroproline4-(N-methoxyamidino)-2-thienylmethylamide hydrochloride a)3,4-Dehydroproline 4-cyano-2-thienylmethylamide hydrochloride

-   -   This compound was prepared in analogy to Example 1a), employing        2-aminomethyl-4-cyanothiophene (WO 98/06741).

b)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline4-cyano-2-thienylmethylamide

-   -   This compound was prepared in analogy to Example 1b).

c)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline4-methylthioiminomethyl-2-thienylmethylamide hydroiodide

-   -   This compound was prepared in analogy to Example 1c) and d).

d)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thienylmethylamide

-   -   This compound was prepared in analogy to Example 8a).

e) N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thienylmethylamide hydrochloride

-   -   The protective groups were eliminated with dioxane/HCl

f) FAB-MS (M+H⁺): 478 Example 14N-(Cyclohexyloxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thienylmethylamide hydrochloride

This compound was synthesized by reacting the compound detailed inExample 13d) with cyclohexanol in 5M hydrochloric acid in dioxane at 50°C., which achieved elimination of the protective groups andtransesterification/esterification of the carboxyl function to give thecyclohexyl ester.

FAB-MS (M+H⁺): 560

Example 15N-(Methoxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thienylmethylamide hydrochloride

Preparation took place in analogy to Example 14.

FAB-MS (M+H⁺): 492

Example 16N-(Isopropyloxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydro-proline4-(N-methoxyamidino)-2-thienylmethylamide hydrochloride

Preparation took place in analogy to Example 14.

FAB-MS (M+H⁺): 520

Example 17N-(tert-Butoxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydro-proline4-hydroxyamidino-2-thienylmethylamide a)(D)-cyclohexylglycyl-3,4-dehydroproline 4-cyano-2-thienylmethylamidehydrochloride

-   -   H-Pyr-NH—CH₂-5-(3-CN)-thioph hydrochloride (Example 13a) and        Boc-(D)Chg-OH were reacted in analogy to Example 1b) to give        Boc-(D)-Chg-Pyr-NH—CH₂-5-(3-CN)-thioph and the Boc protective        group was then eliminated with hydrochloric acid in ether/ethyl        acetate, resulting in H-(D)-Chg-Pyr-NH—CH₂-5-(3-CN)-thioph        hydrochloride as a white solid.

b) N-(tert-Butoxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-cyano-2-thienylmethylamide

-   -   The product obtained in a), H-(D)-Chg-Pyr-NH—CH₂-5-(3-CN)-thioph        hydrochloride (4.8 g, 11.7 mmol), was suspended in 10 ml of        methylene chloride and, after addition of 40 ml of        ammonia-saturated methylene chloride solution, stirred for 20        min, and then magnesium sulfate was added and the solids were        filtered off. Evaporation of the filtrate in vacuo was followed        by codistillation with methylene chloride several times until        ammonia was completely removed.        H-(D)-Chg-Pyr-NH—CH₂-5-(3-CN)-thioph as base was dissolved in 60        ml of methylene chloride, followed by addition of        diisopropylethylamine (6.1 g, 8.0 ml, 47 mmol) and then, while        cooling, dropwise tert-butyl bromoacetate (2.3 g, 11.7 mmol) in        10 ml of methylene chloride. After 24 h, TLC (methylene        chloride/methanol: 9/1) showed 90% of the precursor had reacted.        The reaction solution was adjusted to pH 3 with aqueous        hydrochloric acid and extracted with methylene chloride, with        unreacted precursor remaining in the aqueous phase. The residue        after drying of the organic phase and evaporation in vacuo was        dissolved in a little methylene chloride and precipitated with        n-hexane and the solid was filtered off. 5.2 g of the title        compound were obtained as a white solid.

c) N-(tert-Butoxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-hydroxyamidino-2-thienylmethylamide

-   -   The product obtained in b),        t-BuO₂C—CH₂-(D)-Chg-Pyr-NH—CH₂-5-(3-CN)-thioph (5.2 g, 10.7        mmol), was dissolved in 60 ml of methanol and, after addition of        hydroxylamine hydrochloride (1.86 g, 26.7 mmol) and        diisopropylethylamine ((6.9 g, 9.15 ml, 53.4 mmol), stirred at        room temperature overnight. The reaction solution was evaporated        in vacuo and then the residue was taken up in aqueous        hydrochloric acid at pH 3 and extracted with ethyl acetate, the        aqueous phase was adjusted to pH 8 with sodium bicarbonate and        again extracted several times with ethyl acetate, and this        organic phase was dried over magnesium sulfate and concentrated        in vacuo. The resulting product was dissolved in the minimum        amount of methylene chloride and reprecipitated with ether. 2.9        g of the title compound were obtained as a white solid.

FAB-MS (M+H⁺): 520

Example 18N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(1,2,4-oxadiazol-5-on-3-yl)-2-thienylmethylamide hydrochloride a)N-(tert-Butoxycarbonylmethyl)-N-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline4-hydroxyamidino-2-thienylmethylamide

-   -   A solution of 5.0 g (8.5 mmol) of the product obtained in        Example 13b),        t-BuO₂C—CH₂—N-Boc-(D)-Chg-Pyr-NH—CH₂-5-(3-CN))-thioph, 1.3 g (17        mmol) of hydroxylamine hydrochloride, and 1.98 g (15.3 mmol) of        diisopropylethylamine in 50 ml of ethanol was heated at 55 to        60° C. for five hours. The solution was then concentrated in        vacuo, and the residue was taken up in 50 ml of ethyl acetate        and washed twice with saturated brine. Drying over magnesium        sulfate was followed by removal of the solvent by distillation.        4.6 g (87%) of a pale yellowish amorphous residue were obtained.

b)N-(tert-Butyloxycarbonylmethyl)-N-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(1,2,4-oxadiazol-5-on-3-yl)-2-thienylmethylamide hydrochloride

-   -   4.6 g (7.4 mmol) of the amide oxime obtained in a) were        dissolved in 30 ml of pyridine and, after addition of 1.3 g (8.0        mmol) of carbonyldiimidazole, refluxed for three hours. The        pyridine was distilled off in vacuo, and the residue was taken        up in tert-butyl methyl ether and washed with 5% strength citric        acid solution and saturated brine. The residue after drying over        magnesium sulfate and distilling off the solvent was purified by        column chromatography (dichloromethane/methanol/glacial acetic        acid 95/5/1) to give 3.8 g (79%) of amorphous residue.

c) N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(1,2,4-oxadiazol-5-on-3-yl)-2-thienylmethylamide hydrochloride

-   -   The 1,2,4-oxadiazol-5-one obtained in b) (3.8 g, 5.9 mmol) was        dissolved in 40 ml of glacial acetic acid and, after addition of        40 ml of 4N hydrochloric acid in 1,4-dioxane, left to stand at        room temperature overnight. The solvent was distilled off as far        as possible and toluene was added several times in order to be        able to remove even the last residues of the solvent by        distillation in a rotary evaporator. Purification by column        chromatography (ethanol/25% strength aqueous ammonia solution        50:2.5) resulted in an amorphous powder which was taken up in a        dioxane/water (7:3) mixture. One equivalent of 32% strength        hydrochloric acid was added, and the residue after evaporation        to dryness was digested with acetonitrile to result in 1.9 g        (62%) of a white powder. FAB-MS (M+H⁺): 489

Example 19N-(Methoxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(1,2,4-oxadiazol-5-on-3-yl)-2-thienylmethylamide hydrochloride

0.8 g (1.5 mmol) of the product obtained in Example 18 c) was dissolvedin 50 ml of methanol and, after addition of 5 ml of a solution of 4Nhydrochloric acid in 1,4-dioxane, refluxed for eight hours. The solventwas distilled off as far as possible and toluene was added several timesin order to be able to remove even the last residues of the solvent bydistillation in a rotary evaporator. The residue was digested withacetonitrile and filtered. 0.65 g (79%) of a white powder was obtained.

FAB-MS (M+H⁺): 503

Example 20N-(Cyclohexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydro-proline4-amidino-2-thiazolylmethylamide dihydrochloride

HO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4 am)-thiaz (1.5 g, 3.24 mmol;preparation: WO 9806741, Example 21) was dissolved in 20 ml ofcyclohexanol and, after addition of hydrochloric acid in ether (5N, 10ml), stirred at 60° C. for 6 h. Since the reaction was still incompleteaccording to TLC (methylene chloride/methanol/acetic acid: 100/20/5), afurther 15 ml of 5N hydrochloric acid in ether were added and themixture was stirred at 60° C. for 4 h. After concentration of thereaction mixture in vacuo it was codistilled several times withmethylene chloride and ether to remove adherent hydrochloric acid. Theproduct was then dissolved in a little methylene chloride andprecipitated with ether, and the residue was filtered off with suctionand dried in vacuo. 1.85 g of the title compound were obtained as awhite hygroscopic solid.

FAB-MS (M+H⁺): 545

Example 21N-(Hexadecyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-amidino-2-thiazolylmethylamide dihydrochloride

Preparation took place in analogy to Example 20 by esterification ofHO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-am))-thiaz with 1-hexadecanol,the reaction taking place at 135° C. for 4 h, and the subsequentpurification of the reaction mixture taking place by columnchromatography (silica gel/methylene chloride with increasing methanolcontent).

FAB-MS (M+H⁺): 687

Example 22N-(Undecyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-amidino-2-thiazolylmethylamide diacetate

Preparation took place in analogy to Example 20 by esterification ofHO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-am))-thiaz with 1-undecanol, thereaction mixture being purified by RP-HPLC (acetonitrile, water, aceticacid gradient).

FAB-MS (M+H⁺): 617

Example 23N-((O-Methyltetraethoxy)-oxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-amidino-2-thiazolylmethylamide diacetate

Preparation took place in analogy to Example 20 by esterification ofH₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4 am))-thiaz with tetraethyleneglycol monomethyl ether and subsequent purification of the crude productby RP-HPLC (acetonitrile, water, acetic acid gradient).

FAB-MS (M+H⁺): 653

Example 24N-(Cyclohexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride a)Boc-2-aminomethyl-thiazole-4-carboxamide

-   -   Ethyl bromopyruvate (386 g, 1.98 mol) was added dropwise to a        solution of Boc-glycinethioamide (370 g, 1.94 mol) in 3.9 liters        of ethanol at 10° C., and the mixture was then stirred at        20°–25° C. for 5 h. 299 ml of a 25% strength aqueous ammonia        solution were then added.    -   940 ml of this mixture (corresponds to 19.9% of the total        volume) were distilled to remove 380 ml of ethanol and, after        addition of a further 908 ml of a 25% strength aqueous ammonia        solution, stirred at 20 to 25° C. for 110 h. After cooling to 0°        C., the solid was filtered off, washed twice with water and        dried. 60.1 g of the Boc-protected thiazolecarboxamide were        obtained with an HPLC purity of 97.9% area, corresponding to a        yield over these two stages of 60.5%.

¹H-NMR (DMSO-d₆, in ppm): 8.16 (s, 1H, Ar—H), 7.86 (t, broad, 1H, NH),7.71 and 7.59 (2× s, broad, 1H each, NH₂), 4.42 (d, 2H, CH₂), 1.41 (s,9H, tert butyl)

b) 2-Aminomethyl-4-cyanothiazole hydrochloride

-   -   Boc-2-aminomethylthiazole-4-carboxamide (75.0 g, 0.29 mol) was        suspended in 524 ml of methylene chloride and, at −5 to 0° C.,        triethylamine (78.9 g, 0.78 mol) and 79.5 g (0.38 mol) of        trifluoroacetic anhydride were added. The mixture was stirred        for 1 h and then allowed to warm to 20 to 25° C., 1190 ml of        water were added and the phases were separated. 160 ml of 5-6N        isopropanolic hydrochloric acid were added to the organic phase,        which was boiled for 3 h, left to stir at 20°–25° C. overnight,        cooled at −5 to 0° C. for 2.5 h and filtered to remove solid.        This was washed with methylene chloride and dried. 48.1 g of        2-aminomethyl-4-cyanothiazole were obtained with an HPLC purity        of 99.4% area, corresponding to a yield over these two stages of        94.3%.

¹H-NMR (DMSO-d₆, in ppm): 8.98 (s, broad, 2H, NH₂), 8.95 (s, 1H, Ar—H),4.50 (s, 2H, CH₂)

c) 3,4-Dehydroproline 4-cyano-2-thiazolylmethylamide hydrochloride

-   -   Preparation took place in analogy to Example 1a) by coupling        Boc-3,4-dehydroproline to 2-aminomethyl-4-cyanothiazole        hydrochloride and then eliminating the protective group.

d)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroproline4-cyano-2-thiazolylmethylamide

-   -   Preparation took place in analogy to Example 1b) by coupling        t-BuO₂C—CH₂-(Boc)-(D)-Cha-OH (WO 9806741) to        H-Pyr-NH—CH₂-2-(4-CN)-thiaz hydrochloride.

e)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide

-   -   t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (22.2 g,        36.7 mmol) was dissolved in ethanol (250 ml), and hydroxylamine        hydrochloride (6.41 g, 92.2 mmol) was added and, while this        suspension was cooled (waterbath), diisopropylethylamine (23.8        g, 31.6 ml, 184.5 mmol) was slowly added dropwise. The reaction        solution was stirred at room temperature for 3 h and then        concentrated in vacuo and taken up in methylene chloride/water,        and the aqueous phase was adjusted to pH 3 with 2N hydrochloric        acid and extracted. The organic phase was washed several times        with water, dried over magnesium sulfate and concentrated in        vacuo. The residue was extracted by stirring with n-hexane,        resulting in 22.5 g of        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz as an        almost pure white solid.

f)N-(Cyclohexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

-   -   t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz (2.0 g,        3.15 mmol) was dissolved in cyclohexanol (25 ml) and, after        addition of 10 ml of 5N hydrochloric acid in ether, stirred at        60° C. for 6 h.    -   Since TLC (methylene chloride/methanol/acetic acid: 100/20/5)        showed that the reaction was not yet complete, a further 10 ml        of 5N hydrochloric acid in ether were added, and the mixture was        stirred at 60° C. for 4 h. Evaporation of the reaction mixture        in vacuo was followed by codistillation several times with        methylene chloride and ether to remove adherent hydrochloric        acid. The product was then dissolved in a little methylene        chloride and precipitated with ether, and the residue was        filtered off with suction and dried in vacuo. 1.81 g of the        title compound were obtained as a white hygroscopic solid.

FAB-MS (M+H⁺): 561

Example 25N-(Hexadecyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function inhexadecanol/dioxane with 5M hydrochloric acid at 135° C., and thesubsequent purification of the reaction mixture by column chromatography(silica gel/methylene chloride with increasing methanol content(0-10%)).

FAB-MS (M+H⁺): 703

Example 26N-(Undecyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function inundecanol/dioxane with 5M hydrochloric acid at 65° C., and thesubsequent purification of the reaction mixture by column chromatography(silica gel/methylene chloride with increasing methanol content(0–10%)).

FAB-MS (M+H⁺): 633

Example 27N-(Methoxyethoxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function in ethyleneglycol monomethyl ether/dioxane with 5M hydrochloric acid at 65° C., andthe subsequent purification of the reaction mixture by columnchromatography (silica gel/methylene chloride with increasing methanolcontent (0–10%)).

FAB-MS (M+H⁺): 537

Example 28N-((O-Methyldiethoxy)oxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function indiethylene glycol monomethyl ether/dioxane with 5M hydrochloric acid at65° C., and the subsequent purification of the reaction mixture bycolumn chromatography (silica gel/methylene chloride with increasingmethanol content (0–10%)).

FAB-MS (M+H⁺): 581

Example 29N-(Hexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function inhexanol/dioxane with 5M hydrochloric acid at 60° C., and precipitatingthe product from ether after concentration in vacuo.

FAB-MS (M+H⁺): 563

Example 30N-(Ethoxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function inethanol/dioxane with 5M hydrochloric acid at 60° C., and precipitatingthe product from ether after concentration in vacuo.

FAB-MS (M+H⁺): 507

Example 31N-(3-Fluoropropyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function in3-fluoropropanol/dioxane with 5M hydrochloric acid at 60° C., andprecipitating the product from ether after concentration in vacuo.

FAB-MS (M+H⁺): 539

Example 32N-(Isopropyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function inisopropanol/dioxane with 5M hydrochloric acid at 60° C., andprecipitating the product from ether after concentration in vacuo.

FAB-MS (M+H⁺): 521

Example 33N-(3,3-Dimethylpropyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups and thetransesterification/esterification of the carboxyl function in3,3-dimethylpropyl alcohol/dioxane with 5M hydrochloric acid at 60° C.,and precipitating the product from ether after concentration in vacuo.

FAB-MS (M+H⁺): 549

Example 34N-(Hydroxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, carrying out theelimination of the protective groups with 1M hydrochloric acid at 60° C.and precipitating the product from ether after concentration in vacuo.

FAB-MS (M+H⁺): 479

Example 35N-(Hydroxycarbonylmethyl)-N-(cyclohexyloxycarbonyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-amidino-2-thiazolylmethylamide hydrochloride

HO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4 am)-thiaz (0.5 g, 1.08 mmol;preparation: WO 9806741, Example 21) was suspended in a mixture of 2.5ml of acetone and 2.5 ml of water, and cyclohexyl chloroformate (0.18 g,1.08 mmol) and then, dropwise, diisopropylethylamine (0.14 g, 0.19 ml,1.08 mmol) were added (pH 6–7), whereupon the precursor dissolved. Afterstirring at room temperature overnight, acetone was removed bydistillation in vacuo, the residue was mixed with water, adjusted to pH3 with dilute hydrochloric acid and extracted with methylene chloride,and the organic phase was dried over magnesium sulfate and concentratedin vacuo. The residue was dissolved in a little methylene chloride andprecipitated with ether. 0.6 g of the title compound was obtained as awhite solid.

FAB-MS (M+H⁺): 589

Example 36N-(Propyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxycarbonyl)amidino-2-thiazolylmethylamide a)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroproline4-amidino-2-thiazolylmethylamide

-   -   t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (2.0 g, 3.3        mmol, Example 24d)) was dissolved in methanol (20 ml) and, after        addition of N-acetyl-L-cysteine (0.6 g, 3.66 mmol), refluxed        while passing in ammonia until the precursor had completely        reacted (about 12 h, TLC check: methylene chloride/methanol:        95/5 and methylene chloride/methanol/acetic acid: 100/20/5). The        reaction solution was concentrated in vacuo, the residue was        taken up in dilute hydrochloric acid (pH 3) and extracted with        ether, the aqueous phase was made alkaline with dilute sodium        hydroxide solution (pH 9) and extracted with methylene chloride,        and this organic phase was dried over magnesium sulfate and        concentrated in vacuo. This resulted in 1.8 g of the title        compound as a white solid.

b)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxycarbonyl)amidino-2-thiazolylmethylamide

-   -   The crude product obtained in a),        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NH₂))-thiaz (2.0        g, 3.32 mmol) was dissolved in 50 ml of methylene chloride, and        diisopropylamine (4.2 g, 32.32 mmol) was added and then, while        cooling with a waterbath, methyl chloroformate (0.34 g, 3.56        mmol) in 5 ml of methylene chloride was added dropwise, and the        mixture was stirred at room temperature for 1 h. The residue        after concentration in vacuo was mixed with n-hexane, water and        dilute hydrochloric acid (pH 3), and extracted, the aqueous        phase was then extracted with ethyl acetate, and the ethyl        acetate phase was dried over magnesium sulfate and concentrated        in vacuo. 2.0 g of crude title compound were obtained as a        colorless foam, which was reacted further without further        purification.

c) N-(Propyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxycarbonyl)amidino-2-thiazolylmethylamide

-   -   The crude product obtained in b),        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NH—COOCH₃))-thiaz        (2.0 g, 2.95 mmol), was dissolved in a mixture of 35 ml of        n-propanol and 20 ml of 4.5N hydrochloric acid in ether and        stirred with exclusion of moisture overnight. The reaction        solution was concentrated in vacuo, the residue was taken up in        water and rapidly extracted with ethyl acetate, the aqueous        phase was treated with alkali to pH 7 and extracted several        times with ethyl acetate, and these ethyl acetate phases were        dried over magnesium sulfate and concentrated in vacuo.        Purification of the product by column chromatography on silica        gel (short column, diluent: methylene chloride with increasing        methanol content) resulted in 1.4 g of the title compound as a        white solid.

FAB-MS (M+H⁺): 563

Example 37N-(Cyclohexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxycarbonyl)amidino-2-thiazolylmethylamide

Preparation took place in analogy to Example 36c) fromt-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NH—COOCH₃))-thiaz byelimination of protective groups and subsequenttransesterification/esterification of the carboxyl function incyclohexanol with 4.5M hydrochloric acid in ether.

FAB-MS (M+H⁺): 603

Example 38N-(Methoxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxycarbonyl)amidino-2-thiazolylmethylamide

Preparation took place in analogy to Example 36c) fromt-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NH—COOCH₃))-thiaz byelimination of protective groups and subsequenttransesterification/esterification of the carboxyl function in methanolwith 4.5 M hydrochloric acid in ether.

FAB-MS (M+H⁺): 535

Example 39N-(Methoxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-cyclohexyloxycarbonyl)amidino-2-thiazolylmethylamide

Preparation took place in analogy to Example 36b) and c) fromt-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NH₂))-thiaz by reactionwith cyclohexyl chloroformate and subsequent elimination of protectivegroups and transesterification/esterification of the carboxyl functionin methanol.

FAB-MS (M+H⁺): 603

Example 40N-(tert-Butyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide a)(D)-cyclohexylalanyl-3,4-dehydroproline 4-cyano-2-thiazolylmethylamide

-   -   H-Pyr-NH—CH₂-2-(4-CN)-thiaz-hydrochloride (Example 24c) and        Boc-(D)-Cha-OH were reacted in analogy to Example 1b) to give        Boc-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz, and the Boc protective        group was then eliminated with hydrochloric acid in isopropanol,        resulting in H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz hydrochloride        as a white solid. The product was converted into the base        H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz in analogy to Example 17b)        with ammonia in methylene chloride.

b)N-(tert-Butyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-cyano-2-thiazolylmethylamide

-   -   The product obtained in a), H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz,        was converted in analogy to Example 17b) by alkylation with        bromoacetic acid into        t-BuO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz.

c)N-(tert-Butyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide

-   -   The product obtained in b),        t-BuO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz, and hydroxylamine        were reacted in analogy to Example 24e) to give        t-BuO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz.

FAB-MS (M+H⁺): 535

Example 41N-(Adamantyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide a) Adamantyl bromoacetate

-   -   1-Adamantol (3.0 g, 20.0 mmol) was dissolved in 30 ml of        methylene chloride and, after addition of pyridine (9.5 g, 9.6        ml, 120 mmol) and cooling to −10° C., bromoacetyl bromide (4.4        g, 22.0 mmol) in 15 ml of methylene chloride was added dropwise        to this solution with stirring. Warming to room temperature        (2 h) was followed by addition of aqueous citric acid solution        (pH 2) and extraction, and the organic phase was washed with        water, dried over magnesium sulfate and concentrated in vacuo.        The resulting crude product Ada-O₂C—CH₂—Br was employed without        further purification in the subsequent alkylation.)

b)N-(Adamantyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-cyano-2-thiazolylmethylamide

-   -   Ada-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz was prepared in        analogy to Example 40 starting from        H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz and Ada-O₂C—CH₂—Br.

c)N-(Adamantyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide

-   -   Ada-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz was prepared in        analogy to Example 24e) starting from        Ada-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz and hydroxylamine.

FAB-MS (M+H⁺): 613

Example 42N-(Adamantyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-amidino-2-thiazolylmethylamide diacetate

-   -   Ada-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (Example 41b) was        converted in analogy to Example 36a) with ammonia and        acetylcysteine into        Ada-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz and the resulting        crude product was purified by RP-HPLC.

FAB-MS (M+H⁺): 597

Example 43 N-(Hydroxyethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride a)N-(Hydroxyethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-cyano-2-thiazolylmethylamide

-   -   H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (4.0 g, 10.3 mmol, Example        40a)) was stirred together with iodoethanol (1.5 ml) in an oil        bath at 100° C. for 5 h. Since TLC (methylene        chloride/methanol/acetic acid: 100/20/5) showed precursor still        present, the mixture was cooled and the base was liberated with        ammoniacal methylene chloride solution, and the reaction mixture        was again heated at 100° C. with iodoethanol (1.5 ml) for 2 h.        Volatiles were then removed in vacuo, and the residue was        extracted by stirring with ether three times. 5.3 g of the title        compound were obtained as a pale yellow solid which was employed        without further purification in the following reaction.)

b) N-(Hydroxyethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-hydroxyamidino-2-thiazolylmethylamide hydrochloride

-   -   The crude product obtained in a),        HO—CH₂—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz, was converted in        analogy to Example 24e) with hydroxylamine hydrochloride into        the corresponding hydroxyamidine compound, which was then        converted with hydrochloric acid in ether into the hydrochloride        HO—CH₂—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz hydrochloride.

FAB-MS (M+H⁺): 465

Example 44 N-(Hydroxyethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-amidino-2-thiazolylmethylamide diacetate

HO—CH₂—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (Example 43a) was reactedin analogy to Example 36a) with ammonia and N-acetyl-L-cysteine to giveHO—CH₂—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz, and the resulting crudeproduct was then purified by column chromatography (silica gel;methylene chloride/methanol/acetic acid: 80/20/1), resulting in thetitle compound as a colorless solid.

FAB-MS (M+H⁺): 449

Example 45N-(Hexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thiazolylmethylamide hydrochloride a)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroproline4-aminothiocarbonyl-2-thiazolylmethylamide

-   -   t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (Example        24d)) was reacted in analogy to Example 1c) with hydrogen        sulfide in pyridine/triethylamine to give the corresponding        thioamide        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-CSNH₂)-thiaz.

b)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroproline4-methylthioiminomethyl-2-thiazolylmethylamide hydroiodide

-   -   The product obtained from a),        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-CSNH₂)-thiaz, was        reacted in analogy to Example 1d) with methyl iodide to give        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(SCH₃))-thiaz HI.

c)N-(tert-Butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thiazolylmethylamide

-   -   The product obtained from b),        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(SCH₃))-thiaz was        reacted in analogy to Example 8a) with methoxylamine to give        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-methoxyamidino)-thiaz.

d) N-(Hexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thiazolylmethylamide hydrochloride

-   -   The elimination of protective groups and the        transesterification/esterification of the carboxyl function in        t-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NHOCH₃))-thiaz        was carried out in analogy to Example 24f) in hexanol with 5M        hydrochloric acid in ether at 60° C., and the resulting crude        product was purified by extraction (methylene chloride/water)        and subsequent precipitation from ether, resulting in the title        compound as a white solid.

FAB-MS (M+H⁺): 577

Example 46N-(Ethoxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thiazolylmethylamide hydrochloride

The elimination of protective groups and thetransesterification/esterification of the carboxyl function int-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NHOCH₃))-thiaz wascarried out in analogy to Example 24f) in ethanol with 5M hydrochloricacid in ether at 60° C., and the resulting crude product was purified byextraction (methylene chloride/a little water) and subsequentprecipitation from ether, resulting in the title compound as a whitesolid.

FAB-MS (M+H⁺): 521

Example 47N-(Cyclohexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(N-methoxyamidino)-2-thiazolylmethylamide hydrochloride

The elimination of protective groups and thetransesterification/esterification of the carboxyl function int-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-C═NH(NHOCH₃))-thiaz wascarried out in analogy to Example 24f) in cyclohexanol with 5Mhydrochloric acid in ether at 60° C., and the resulting crude productwas purified by extraction (methylene chloride/a little water) andsubsequent precipitation from ether, resulting in the title compound asa white solid.

FAB-MS (M+H⁺): 575

Example 48N-(Hydroxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(1,2,4-oxadiazol-5-on-3-yl)-2-thiazolylmethylamide hydrochloride

Preparation took place starting fromt-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz (Example 24d) inanalogy to Example 18), resulting in the title compound as a whiteamorphous powder.

FAB-MS (M+H⁺): 505

Example 49N-(Methoxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline4-(1,2,4-oxadiazol-5-on-3-yl)-2-thiazolylmethylamide hydrochloride

Preparation took place starting fromt-BuO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz (Example 24d) inanalogy to Example 19), resulting in the title compound as a whiteamorphous powder.

FAB-MS (M+H⁺): 519

Example 50N-(Hydroxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline4-(N-tert-butyloxycarbonylmethyleneamidino)-2-thienylmethylamidehydrochloride

This compound was prepared by dissolving 2.47 g (3.24 mmol) of theproduct obtained in 13c),N-(tert-butoxycarbonylmethyl)-(Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline4-methylthioiminomethyl-2-thienylmethylamide hydroiodide, in 40 ml ofmethanol and, at room temperature, adding 2.86 g (19.43 mmol) oftert-butyl aminoxyacetate, and heating at 40° C. for 20 min. The residueafter concentration was taken up in ethyl acetate and washed twice with10% strength sodium thiosulfate solution and once each with 20% strengthsodium bisulfate solution and saturated sodium chloride solution. Theresidue (2.5 g) after drying over magnesium sulfate and concentratingthe solution was purified by column chromatography (eluent: hexane/ethylacetate 1:1). 2.3 g of a yellowish oil were obtained. The protectivegroups were eliminated with dioxane/HCl at room temperature within threehours.

FAB-MS (M+H⁺): 522

Example 51N-(n-Hexyloxycarbonylmethyl)-(D)-cyclohexylgycyl-3,4-dehydroproline5-(3-hydroxyamidino)thienylmethylamide

10 ml (40 mmol) of a 4 molar solution of hydrogen chloride in1,4-dioxane were added to a solution of 2.5 g (4 mmol) of the productN-(tert-butoxycarbonylmethyl)-(N-Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline5-(3-hydroxyamidino)thienylmethylamide obtained according to Example 18ain 25 ml 1-hexanol and the reaction mixture was heated to 40° C. Thereaction mixture was stirred for 8 hours at this temperature andovernight at room temperature. Although no complete conversion wasobserved, the reaction mixture was concentrated to dryness on a rotaryevaporator, was taken up in diethyl ether and stirred. The precipitatewas filtered off, washed with ether, dissolved in methanol andtransferred into the acitic acid salt via an ion exchange. The residuewas purified by column chromatography (normal phase-MPLC, eluent:dichloromethane/methanol=95:5). 1.8 g (73%) of the title compound wereobtained as a white solid.

ESI-MS (M+H⁺): 548

Example 52N-(Ethoxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline5-(3-hydroxyamidino)thienylmethylamide

10 ml (40 mmol) of a 4 molar solution of hydrogen chloride in1,4-dioxane were added to a solution of 2.5 g (4 mmol) of the productN-(tert-butoxycarbonylmethyl)-(N-Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline5-(3-hydroxyamidino)thienylmethylamide obtained according to Example 18ain 25 ml ethanol and the reaction mixture was heated to 40° C. Thereaction mixture was stirred for 8 hours at this temperature andovernight at room temperature. Although no complete conversion wasobserved, the reaction mixture was concentrated to dryness on a rotaryevaporator, was taken up in diethyl ether and stirred. The precipitatewas filtered off, washed with ether, dissolved in methanol andtransferred into the acetic acid salt using an ion exchanger. Theresidue was purified by column chromatography (normal phase-MPLC,eluent: dichloromethane/methanol=95:5). 0.59 g (27%) of the titlecompound were obtained as a white solid.

ESI-MS (M+H⁺): 492

Example 53N-(Cyclopentyloxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline5-(3-hydroxyamidino)thienylmethylamide

10 ml (40 mmol) of a 4 molar solution of hydrogen chloride in1,4-dioxane were added to a solution of 2.5 g (4 mmol) of the productN-(tert-butoxycarbonylmethyl)-(N-Boc)-(D)-cyclohexylglycyl-3,4-dehydroproline5-(3-hydroxyamidino)thienylmethylamide obtained according to Example 18ain 25 ml cyclopentanol and the reaction mixture was heated to 40° C. Thereaction mixture was stirred for 2 days at this temperature. Although nocomplete conversion was observed, the reaction mixture was concentratedto dryness on a rotary evaporator, was taken up in diethyl ether andstirred. The precipitate was filtered off, washed with ether, dissolvedin methanol and transferred into the acetic acid salt using an ionexchanger. The residue was purified by column chromatography (normalphase-MPLC, eluent: ethyl acetate/n-hexane=8:2). 1.38 g (58%) of thetitle compound was obtained as a white solid.

ESI-MS (M+H⁺): 532

Example 54N-(Cyclohexyloxycarbonylmethyl)-(D)-cyclohexylglycyl-3,4-dehydroproline5-(3-hydroxyamidino)thienylmethylamide

Preparation took place by using t-BuO₂C—CH₂—(Boc)-(D)-Chg-Pyr-NH—CH₂-5-(3-ham)-thioph (Example 18a) and cyclohexanolin analogy to Example 53, whereby the title compound was obtained as awhite amorphous powder.

ESI-MS (M+H⁺): 546

Example 55N-(Cyclopropylmethyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 53, starting fromN-(hydroxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride (Example 34) andcyclopropyl methanol, whereby the title compound was obtained as a whiteamorphous powder.

ESI-MS (M+H⁺): 533

Example 56N-(Cyclopentyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 53, starting fromN-(hydroxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride (Example 34) andcyclopentanol, whereby the title compound was obtained as a whiteamorphous powder.

ESI-MS (M+H⁺): 547

Example 57N-(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyloxycarbonylmethyl-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)-thiazolylmethylamide hydrochloride a)4-Bromomethyl-5-methyl-2-oxo-1,3-dioxolon

4-Bromomethyl-5-methyl-2-oxo-1,3-dioxolon was prepared according toSakamoto, Ikeda and Tsukamoto (Chem. Pharm. Bull. 1984, 32, 6,2241–2248) via radical bromination from 11.4 g4,5-dimethyl-2-oxo-1,3-dioxolon and 17.6 g bromine.

b) 4-Hydroxymethyl-5-methyl-2-oxo-1,3-dioxolon

4-Bromomethyl-5-methyl-2-oxo-1,3-dioxolon obtained in a) was convertedto the title compound via the formylester as the intermediate in analogyto Alexander et al. (J. Med. Chem. 1996, 39, 480–86).

c) Methyl 5-methyl-2-oxo-1,3-dioxolon-4-yl bromoacetate

4-Hydroxymethyl-5-methyl-2-oxo-1,3-dioxolon (0.44 g, 3.4 mmol) wasdissolved in 5 ml dichloromethane mixed with pyridine (0.27 g, 0.3 ml,3.4 mmol), cooled to 0° C. and subsequently bromoacetic acid bromide(0.68 g, 3.4 mmol) dissolved in 3 ml dichloromethane was added dropwisewhilst stirring. The reaction mixture was diluted with ethyl acetateafter warming to room temperature (1.5 h) and was extracted severaltimes with a little water to separate pyridine. The combined organicextracts were dried over magnesium sulphate and concentrated in vacuoafter filtering off the drying agent. The obtained crude product1,3-Dioxol-2-on-4-yl-O₂C—CH₂—Br was used without further purification inthe subsequent alkylation.

d)N-(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyloxycarbonylmethyl-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-cyano)-thiazolylmethylamide

Starting from H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz and1,3-dioxol-2-on-4-yl-O₂C—CH₂—Br,1,3-dioxol-2-on-4-yl-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz wasprepared in analogy to Example 40.

e)N-(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyloxycarbonylmethyl-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)-thiazolylmethylamide

Starting from1,3-dioxol-2-on-4-yl-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz andhydroxylamine,1,3-dioxol-2-on-4-yl-O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz wasprepared in analogy to Example 24e).

ESI-MS (M+H⁺): 591

Example 58N-(Hydroxycarbonylmethyl)-N-(methyloxycarbonyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 35, starting fromHO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz and methyl chloroformiatewhereby the title compound was obtained as a white amorphous powder.

FAB-MS (M+H⁺): 521

Example 59N-(Hydroxycarbonylmethyl)-N-(hexyloxycarbonyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 35, starting fromHO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz and hexyl chloroformiatewhereby the title compound was obtained as a white amorphous powder.

FAB-MS (M+H⁺): 591

Example 60N-(Methoxyethoxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide dihydrochloride

Preparation took place in analogy to Example 20 by esterification ofHO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz with ethyleneglycolmonomethyl ether whereby the conversion took place at about 60-65° C.and the subsequent purification of the reaction mixture was conductedusing column chromatography (silica gel/dichloromethane with increasingamount of methanol).

FAB-MS (M+H⁺): 521

Example 61N-((O-Methyldiethoxy)-oxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide dihydrochloride

Preparation took place in analogy to Example 20 by esterification ofHO₂C—CH₂-(Boc)-(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz with diethyleneglycolmonomethyl ether whereby the conversion took place at about 60–65° C.After exchanging the chloride ions with acetate ions using an ionexchanger, the purification of the reaction mixture was conducted usingHPLC (RP Phase, Lyophilising the aqueous solution with addition ofhydrochloric acid) and the product was obtained as a white solid.

FAB-MS (M+H⁺): 565

Example 62N-(6-Aminohex-1-yl-oxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide×acetic acid

Preparation of BOC-NH— (CH₂)₆—O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaztook place at first in analogy to Example 41a, by conversion ofBOC-NH—(CH₂)₆—OH with bromoacetic acid bromide toBOC-NH—(CH₂)₆—OCO—CH₂—Br which was subsequently used in an analogy toExample 17b or 40b, respectively, in the alkylation withH-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz. After conversion of the obtainedintermediate BOC-NH—(CH₂)₆—O₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiazwith (BOC)₂O toBOC-NH—(CH₂)₆—O₂C—CH₂-(BOC)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz, thenitrile function was converted to the amidine function in an analogy toWO 9806741. After removal of the protecting group with hydrochloric acidin dioxane, exchange of the chloride ions with acetate ions using an ionexchanger and subsequent chromatographic purification (HPLC: RP phase,lyophilising the aqueous solution) the title compound H₂N—(CH₂)₆—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-am)-thiaz×CH₃COOH was obtained as a whitepowder.

FAB-MS (M+H⁺): 562

Example 63N-(Decahydro-2-naphthyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in decahydro-2-naphthol/dioxane with 5 Mhydrochloric acid at 60° C. After concentrating in vacuo, the residuewas stirred with ether to remove excess hydrochloric acid and alcohol,the residue was dissolved in aqueous potassium carbonate solution (pH8), extracted several times with dichloromethane, the organic phaseswere dried over magnesium sulphate, etheral hydrochloric acid was addedand the residue was concentrated. The residue was co-distilled severaltimes with ether and subsequently stirred with ether wherebyC₁₀H₁₇—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtained as awhite solid substance.

FAB-MS (M+H⁺): 615

Example 64N-(Cyclohexylmethyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in cyclohexylmethyl alcohol/dioxane with5 M hydrochloric acid at 60° C. The work-up was conducted as describedin Example 63, wherebyC₆H₁₁—CH₂—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtained asa white solid substance.

FAB-MS (M+H⁺): 575

Example 65N-(4-tert-Butylcyclohexylcarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in 4-tert-butyl cyclohexanol/dioxane with5 M hydrochloric acid at 60° C. The work-up was conducted as describedin Example 63, whereby 4-(CH₃)₃C—C₆H₁₀—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtained as a white solidsubstance which according to HPLC or NMR is a mixture of 75% of thetrans and 25% of the cis ester.

FAB-MS (M+H⁺): 617

Example 66N-(Adamant-1-ylmethyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-amidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in adamantyl-1-methyl alcohol/dioxanewith 5 M hydrochloric acid at 60° C. The work-up was conducted asdescribed in Example 63, wherebyC₁₀H₁₅—CH₂—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtained asa white substance.

FAB-MS (M+H⁺): 627

Example 67N-(4-tert-Butylcyclohexylmethyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in 4-tert-butyl cyclohexylmethylalcohol/dioxane with 5 M hydrochloric acid at 60° C. The work-up wasconducted as described in Example 63, whereby4-(CH₃)₃C—C₆H₁₀—CH₂—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl wasobtained as a white solid substance.

FAB-MS (M+H⁺): 631

Example 68N-(4-Methoxycyclohexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in 4-methoxy cyclohexanol/dioxane with 5M hydrochloric acid at 60° C. The work-up was conducted as described inExample 63, whereby4-CH₃O—C₆H₁₀—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtainedas a white solid substance.

FAB-MS (M+H⁺): 591

Example 69N-(4-Cycloheptyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification wasconducted in cycloheptanol/dioxane with 5 M hydrochloric acid at 60° C.The work-up was conducted as described in Example 63, wherebyC₇H₁₃—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtained as awhite solid substance.

FAB-MS (M+H⁺): 575

Example 70N-(3.3.5.5-Tetramethylcyclohexyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in 3.3.5.5-Tetramethylcyclohexanol/dioxane with 5 M hydrochloric acid at 60° C. The work-upwas conducted as described in Example 63, whereby3.3.5.5-(CH₃)₄—C₆H₁₀—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl wasobtained as a white solid substance.

FAB-MS (M+H⁺): 617

Example 71N-(4-Pyranyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in 4-pyranylalcohol/dioxane with 5 Mhydrochloric acid at 60° C. The work-up was conducted as described inExample 63, whereby4-pyranyl-O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtained asa white solid substance.

FAB-MS (M+H⁺): 563

Example 72N-(Methyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in methanol/dioxane with 5 M hydrochloricacid at 60° C. CH₃—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl wasobtained as a white solid substance by stirring with ether.

FAB-MS (M+H⁺): 493

Example 73N-(n-Propyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in propanol/dioxane with 5 M hydrochloricacid at 60° C. After stirring with etherCH₃—CH₂—CH₂—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl was obtainedas a white solid substance.

FAB-MS (M+H⁺): 521

Example 74N-(n-Butyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in n-butanol/dioxane with 5 Mhydrochloric acid at 60° C. After stirring with etherCH₃—CH₂—CH₂—CH₂—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl wasobtained as a white solid substance.

FAB-MS (M+H⁺): 535

Example 75N-(i-Butyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide hydrochloride

Preparation took place in analogy to Example 24, whereby the removal ofthe protecting groups and the transesterification/esterification of thecarboxy function was conducted in iso-butanol/dioxane with 5 Mhydrochloric acid at 60° C. After stirring with etherCH₃—CH(CH₃)—CH₂—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl wasobtained as a white solid substance.

FAB-MS (M+H⁺): 535

Example 76N-(2.4-Dimethylpent-3-yloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide a) 2.4-Dimethylpent-3-ylbromoacetate

-   -   2.4-dimethylpentan-3-ol (4.0 g, 4.8 ml, 34.4 mmol), n-pentane        (40 ml) and pyridine (16.3 g, 16.6 ml, 206.5 mmol) were placed        in a flask, cooled to −10° C. and bromoacetyl bromide (9.0 g,        3.9 ml, 44.75 mmol) was slowly added to the solution. After        stirring for 5 h at room temperature more pentane was added, the        organic solution was subsequently dried over a magnesium        sulphate and carefully concentrated in vacuo. 7.2 g of        [(CH₃)₂CH]₂CH—O₂C—CH₂—Br was obtained as a colorless liquid.

b) [(CH₃)₂CH]₂CH—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz

-   -   H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (Example 40a) was alkylated        in analogy to Example 40b with [(CH₃)₂CH]₂CH—O₂C—CH₂—Br to        [(CH₃)₂CH]₂CH—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz and        subsequently converted with hydroxylamine in analogy to Example        24e to [(CH₃)₂CH]₂CH—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz.        After concentrating the reaction mixture in vacuo, the residue        was taken up in dichloromethane, extracted with a solution of        hydrochloric acid (pH 1–2), the aqueous phase containing the        title compound was subsequently set to pH 5 and again extracted        with dichloromethane. After drying over magnesium sulphate and        concentrating the solution in vacuo,        [(CH₃)₂CH]₂CH—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz was        obtained as a white solid substance.

FAB-MS (M+H⁺): 577

Example 77N-(1-Methylcyclopentyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide

1-Methylcyclopentyl bromoacetate prepared in analogy to 76a wasconverted with H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (Example 40a) to(1-CH₃)C₅H₈—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz which was in turnsubsequently converted to(1-CH₃)C₅H₈—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz in analogy toExample 24e. The isolation of the product was conducted in analogy toExample 76b.

FAB-MS (M+H⁺): 561

Example 78N-(áá-Dicyclohexylmethyloxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide

áá-Dicyclohexylmethyl bromoacetate prepared in analogy to 76a wasconverted with H-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (Example 40a) to(C₆H₁₁)₂CH—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz which in turn wassubsequently converted to(C₆H₁₁)₂CH—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz in analogy toExample 24e. The isolation of the product was conducted in analogy toExample 76b.

FAB-MS (M+H⁺): 657

Example 79N-(tert-Butylaminocarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide a)N-(Hydroxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-cyano)thiazolylmethylamide

-   -   (CH₃)₃C—O₂C—CH₂-(BOC)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (7.0 g,        11.6 mmol; Example 24d) was dissolved in dichloromethane (70        ml), dioxane/hydrochloric acid (14.4 ml, 4 M) was added and the        mixture was stirred overnight at room temperature. The        intermediate which had formed an oil was taken from the walls of        the flask and the mixture was again stirred for 4 h.        Subsequently, the solution was concentrated in vacuo and        co-distilled several times with ether. The product was purified        by column chromatography (silica gel; eluent: dichloromethane        with increasing amount of methanol).

b)N-(Hydroxycarbonylmethyl)-(BOC)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-cyano)thiazolylmethylamide

-   -   HO₂C—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (4.2 g, 8.7 mmol; see        a)) was suspended in dichloromethane (40 ml), diisopropyl        ethylamine (11.3 g, 14.9 ml, 87.2 mmol) was added and (BOC)₂O        (3.8 g, 54.5 mmol) in dichloromethane (5 ml) was dropwise added        to the solution at room temperature. After stirring for 5 h at        room temperature the conversion was complete (monitored by TLC).        The reaction solution was concentrated in vacuo, aqueous        hydochloric acid (pH 3) was added to the residue, the residue        was extracted several times with ether, the organic phases were        dried over magnesium sulphate and to the residue, the residue        was extracted several times with ether, the organic phases were        dried over magnesium sulphate and concentrated in vacuo, whereby        the title compound was obtained as a white solid substance.

c)N-(tert-Butylaminocarbonylmethyl)-(BOC)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-cyano)thiazolylmethylamide

-   -   HO₂C—CH₂-(BOC)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (1.0 g, 1.8        mmol; see b)) was dissolved together with tert-butylamine (5 ml,        47 mmol) in dichloromethane (47 ml), cooled to 5° C. and        propylphosphonic acid anhydride solution in ethyl acetate (50%        solution, 1.7 ml, 2.16 mmol) was slowly added at 5° C. After        stirring for 1 h at 10° C. conversion was complete according to        TLC analysis. The residue was concentrated in vacuo, taken up in        ether, consecutively washed in water, 0.3 N hydrochloric acid        and water, dried over magnesium sulphate and concentrated in        vacuo, whereby the title compound was obtained as a white foam.

d)N-(tert-Butylaminocarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide

-   -   (CH₃)₃C—NH—CO—CH₂-(BOC)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz was        converted with hydroxylamine to        (CH₃)₃C—NH—CO—CH₂-(BOC)-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz in        analogy to Example 24e, from which the title compound was        obtained as a white solid substance by removal of the protecting        group with hydrochloric acid in dioxane/dichloromethane.

FAB-MS (M+H⁺): 534

Example 80N-(n-Hexylaminocarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide

Preparation took place by couplingHO₂C—CH₂-(BOC)-(D)-Cha-Pyr-NH—CH₂-2-(4-CN)-thiaz (Example 79b) withn-hexylamine, subsequent conversion with hydroxylamine toCH₃—(CH₂)₅—NH—CO—CH₂-(BOC)-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz which bycleavage of the protection group was converted toCH₂—(CH₂)₃—NH—CO—CH₂—(D)—Cha-Pyr-NH—CH₂-(4-ham)-thiaz.

Example 81N-(Hydroxyaminocarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thiazolylmethylamide

CH₃—O₂C—CH₂(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz×HCl (1.8 g, 3.4 mmol,Example 72), methanol (20 ml), hydroxylamine hdrochloride (3.6 g, 54mmol) and diisopropyl ethylamine (10.5 g, 13.9 ml, 81 mmol) were stirredovernight at room temperature. After filtering the reaction mixture,concentrating under high vacuum (preferably complete removal ofdiisopropyl ethylamine), dissolving the residue in water, the reactionmixture was converted into the acetate using an ion exchange column. Thelater fractions contained the desired product with only a little contentof diisopropyl ethylammonium acetate which was removed by lyophilisationof the solution. HONH—OC—CH₂-(D)-Cha-Pyr-NH—CH₂-2-(4-ham)-thiaz (1.0 g)was obtained as a white solid substance.

FAB-MS (M+H⁺): 494

Example 82N-(Hydroxycarbonylmethyl)-(D)-cyclohexylalanyl-3,4-dehydroproline2-(4-hydroxyamidino)thienylmethylamide hydrochloride

Preparation took place starting from(CH₃)₃C—O₂C—CH₂-(D)-Chg-Pyr-NH—CH₂-5-(3-ham)-thioph by removal of theprotecting group with 1 M hydrochloric acid at 60° whereby the productwas precipitated from ether after concentration in vacuo.

FAB-MS (M+H⁺): 464

1. Compounds of the formula I or II

in which A, B, D, E, G and K have the following meanings: A: R¹OOC—CH₂—,R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—, R¹OOC—C(CH₃)₂—, C₁₋₄₋alkyl-SO₂—(CH₂)₂₋₆,5-tetrazyolyl-(CH₂)₁₋₆—, C₁₋₄-alkyl-O—(CH₂)₂₋₆—, H₂N—(CH₂)₂₋₃—,CH₃—NH—(CH₂)₂₋₃—, (CH₃)₂N—(CH₂)₂₋₃—, H₂NSO₂—(CH₂)₂₋₄—,CH₃—NHSO₂—(CH₂)₂₋₄—, in which R¹: is H—, C₁–C₈-alkyl-,C₅–C₈-cycloalkyl-, C₅–C₈-cycloalkyl-C₁–C₃-alkyl-, it being possible forall the radicals mentioned apart from H to carry optionally up to fouridentical or different radicals selected from CH₃, CF₃, F, Cl, ormethoxy radicals, or R¹ is 2-oxo-1,3-dioxo-4-yl-methyl which may besubstituted in the 5-position by C₁–C₃-alkyl or aryl, or R¹: isR^(1b)—C(O)O—CH₂—, R^(1b)—C(O)O—CH(CH₃)—, where R^(1b) can beC₁–C₄-alkyl-, C₅–C₈-cycloalkyl-, C₁–C₄-alkyloxy- orC₅–C₈-cycloalkyloxy-,

in which p is 0,1, R⁴ is H—, R⁵ is H—, R⁶ is cyclopentyl, cyclohexyl,cycloheptyl, R⁷ is H, R⁸ is H,

in which R¹⁴: is H, CH₃, Cl, G: is —OH, —C(O)OR²⁰, in which R²⁰ is—C₁₋₈-alkyl, —C₁–C₃-alkyl-C₅–C₈-cycloalkyl, —C₅–C₈-cycloalkyl, K is H,where the following applies, with retention of the meanings of D: (i)when E is II, and G is —OH, C(O)OR²⁰, where R²⁰ has the same meaning asabove, and K is H, then A and B have the following meanings: A:R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—, R¹OOC—C(CH₃)₂—,C₁₋₄-alkyl-SO₂—(CH₂)₂₋₄—, 5-tetrazyolyl-(CH₂)₁₋₃—,C₁₋₄-alkyl-O—(CH₂)₂₋₄—, H₂N—(CH₂)₂₋₃, CH₃—NH—(CH₂)₂₋₃, (CH₃)₂N—(CH₂)₂₋₃,H₂N—SO₂—(CH₂)₂₋₄, CH₃—NH—SO₂—(CH₂)₂₋₄, in which R¹: is H—, C₁–C₈-alkyl-,C₅–C₈-cycloalkyl-, C₅–C₈-cycloalkyl-C₁–C₃-alkyl-, it being possible forall the radicals mentioned apart from H to carry optionally up to fouridentical or different radicals selected from CH₃, CF₃, F, Cl, ormethoxy radicals, or R¹ is 2-oxo-1,3-dioxol-4-yl-methyl which may besubstituted in position 5 by C₁–C₁₆-alkyl or aryl, or R¹: isR^(1b)—C(O)O—CH₂—, R^(1b)—C(O)O—CH(CH₃)—, where R^(1b) can beC₁–C₄-alkyl, C₅–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₅–C₈-cycloalkoxy,

in which p: is 0, 1, R⁴: is H—, R⁵: H, R⁶: cyclopentyl, cyclohexyl,cycloheptyl, R⁷: H, and R⁸: H, (ii) when E is VI, and G is OH and K isH, then A and B have the following meanings: A: R¹OOC—CH₂,R¹OOC—CH₂—CH₂, R¹OOC—CH(CH₃), R¹OOC—C(CH₃)₂, in which R¹: isC₇–C₈-alkyl, C₅–C₈-cycloalkyl, C₅–C₈-cycloalkyl-C₁–C₃-alkyl, it beingpossible for all the radicals mentioned apart from H to carry optionallyup to three identical or different radicals selected from CH₃, CF₃, F,Cl, or methoxy radicals, or 2-oxo-1,3-dioxol-4-yl-methyl- which may besubstituted in position 5 by C₁–C₁₆-alkyl or aryl, or R¹: isR^(1b)—C(O)O—CH₂, R^(1b)—C(O)O—CH(CH₃)—, where R^(1b) can beC₁–C₄-alkyl, C₅–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₅–C₈-cycloalkoxy,

in which p: 0, 1, R⁴: is H—, R⁵: H, R⁶: cyclopentyl, cyclohexyl,cycloheptyl, R⁷: H, and R⁸: H, (iii) when E is VI, and G is —C(O)OR²⁰,where R²⁰ has the same meaning as above, and K is H, then A and B havethe following meanings: A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,R¹OOC—C(CH₃)₂,— in which R¹: is H—, C₁–C₈-alkyl-, C₅–C₈-cycloalkyl-,C₅–C₈-cycloalkyl-C₁–C₃-alkyl-, it being possible for all the radicalsmentioned apart from H to carry optionally up to three identical ordifferent radicals selected from CH₃, CF₃, F, Cl, or methoxy radicals,or R¹ is 2-oxo-1,3-dioxol-4-yl-methyl which may be substituted inposition 5 by C₁–C₁₆-alkyl or aryl, or R¹ is R^(1b)—C(O)O—CH₂—,R^(1b)—C(O)O—CH(CH₃)—, where R^(1b) can be C₁–C₄-alkyl,C₅–C₈-cycloalkyl, C₁–C₄-alkyloxy, C₅–C₈-cycloalkoxy,

in which p: is 0, 1, R⁴: is H, R⁵: H, R⁶: cyclopentyl, cyclohexyl,cycloheptyl, R⁷H, and R⁸: H, and the physiologically tolerated saltsthereof.
 2. Compounds of the formula as claimed in claim 1, wherein A,B, D, E, G and K have the following meanings: A: R¹OOC—CH₂—,R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—, R¹OOC—C(CH₃)₂— in which R¹: isC₁–C₈-alkyl-, C₅–C₈-cycloalkyl-, C₅–C₈-cycloalkyl-CH₂-alkyl-, it beingpossible for all the radicals mentioned to carry optionally up to fouridentical or different radicals selected from CH₃ or methoxy radicals,

in which p is 0, 1, R⁴ is H—, R⁵ is H—, R⁶ is cyclohexyl, R⁷ is H, R⁸ isH,

G is —OH, K is H, where the following applies, with retention of themeanings of D: (i) when E is II and G is —OH, then A and B have thefollowing meanings: A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,R¹OOC—C(CH₃)₂—, in which R¹: is C₁–C₈-alkyl-, C₅–C₈-cycloalkyl-,C₅–C₈-cycloalkyl-C₁-alkyl-, it being possible for all the radicalsmentioned apart from H to carry optionally up to four identical ordifferent radicals selected from CH₃ or methoxy radicals,

in which p: is 0, 1, R⁴: is H—, R⁵: H, R⁶: cyclohexyl, R⁷: H, and R⁸: H,(ii) when E is VI, and G is OH and K is H, then A and B have thefollowing meanings: A: R¹OOC—CH₂—, R¹OOC—CH₂—CH₂—, R¹OOC—CH(CH₃)—,R¹OOC—C(CH₃)₂—, in which R¹: is C₇–C₈-alkyl, C₅–C₈-cycloalkyl,C₅–C₈-cycloalkyl-C₁-alkyl, it being possible for all the radicalsmentioned apart from H to carry optionally up to three identical ordifferent radicals selected CH₃ or methoxy radicals,

in which p: 0, 1, R⁴: is H, R⁵: H, R⁶: cyclohexyl, R⁷: H, and R⁸: H andthe physiologically tolerated salts thereof.
 3. A pharmaceuticalcomposition comprising compounds of the formula I as claimed in claim 1in addition to conventional carriers and excipients.
 4. A method oftreating a disease selected from the groups consisting of deep veinthrombosis; pulmonary embolism, Alzheimer's disease; myocardial orcerebral infarction; atrial fibrillation and bypass occlusion thatcomprises administering an effective amount of a compound of claim 1 toa patient in need thereof.